Role of Inflammatory Mediators in Disease Progression and Therapeutic Intervention

Abstract

Inflammation is a highly sophisticated biological reaction with a major role in homeostasis development and pathogen resistance, but its mis regulation is a significant contributor to the aetiology of various acute and long-term diseases. The activation and development of inflammatory responses have a significant impact by inflammatory mediators, including cytokines, chemokines, prostaglandins, leukotrienes, nitric oxide, and reactive oxygen species. These mediators control cellular communication, immune cell recruitment, and vascular modifications and, thus, have effects on disease outcomes. Continuous stimulation of the inflammatory pathways has been linked to progression of Numerous illnesses, such as autoimmune disorders, tumour, heart disorders, and neurological disorders. Significant signal transduction pathways, such as NF-kappa B, MAP kinase and JAK/STAT pathways, these are critical in regulating the inflammatory mediator’s expression and enhancing inflammatory cascades. Corticosteroids, NSAIDs and biologics are used for the treatment of the disease, although their treatment is frequently characterized by such side effects as immunosuppression, adverse effects, high cost, and chronic toxicity. The recent developments have put the emphasis on the possibility of new treatment modalities such as selective cytokine inhibitors, inflammasome inhibitors, gene therapy and nanoparticle-based drug delivery systems, as they persist with better specificity and less systemic side effects. Also, naturally occurring compounds, including curcumin and resveratrol, have demonstrated promising anti-inflammatory properties in that they act on several signalling pathways. This literature review gives an extensive description of the categorization of inflammatory mediators, disease progression, the signalling pathways behind these mediators, and the existing and future treatment, and therapeutic options.

Keywords

Inflammatory mediators, NF-?B signalling, MAPK pathway, JAK-STAT pathway, Therapeutic targets, NLRP3 inflammasome.

Introduction

1. Role of inflammatory mediators in disease progression:

3.1 Eicosanoids:

20-carbon polyunsaturated fatty acids, primarily arachidonic acid, are used in cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 enzymatic processes to produce eicosanoids, which are physiologically active lipid mediators. These are lipoxins, leukotrienes (LTs) and thromboxane’s (TXs). These are locally-autacoid mediators that have decisive functions on inflammation, immune regulation, vascular tone, and tissue homeostasis. Leukotriene B 4 (LTB 4) is a potent neutrophil chemotactic factor. Vasoconstriction and platelet aggregation are encouraged by thromboxane A 2 (TXA 2) ¹⁹. Deregulation of the eicosanoid biosynthesis has a significant part in the initiating, intensifying, and sustaining the inflammatory response that causes a variety of clinical diseases to worsen. The first step in the series of events that result in the tissue's secretion of different cytokines and bloodstream to set off the cascade of events (Batsman, n.d.). <|human|> The release of different cytokines into the blood and tissue is the first step in the cascade of processes that cause inflammation (Batsman, n.d.). The presence of tissue injury stimulates phospholipase A 2 that results in the production of prostaglandins, leukotrienes (2) and release of arachidonic acid. PGE 2 encourages vasodilation, oedema and fever. Too much of these mediators perpetuates the main mechanisms of process of inflammation and leads to the severe inflammatory disease ²⁰. When someone has rheumatoid arthritis, the rise in COX-2 expression causes a rise in the amount of PGE2, which supports synovial inflammation, cartilage erosion, and bone erosion. Continued leukotrienes generation increases inflammation of leukocytes and destruction of joints ²¹. COX-2 overproduction and PGE2 increase is witnessed in various malignancies. PGE II stimulates tumour cell growth, angiogenesis, anti-apoptotic effects, and immunosuppression, leading to the development of tumour growth and metastasis ²². Eicosanoids also aid in chronic, low-grade inflammation related to diabetes mellitus. Prostaglandins and leukotrienes are pro-inflammatory and accelerate the process of insulin resistance and vascular complications like diabetic kidney disease and diabetic eye disease ²³.

3.2 Vasoactive amines:

The biologically active amines produced by the amino acids that control the vascular tone, endothelial permeability, immune reactions, and neurotransmission are vasoactive amines, including histamine, serotonin (5-hydroxytryptamine; 5-HT), and catecholamines (norepinephrine and epinephrine), and are essential in disease progression ^24,25. These mediators execute biological functions by interact with particular G-protein coupled receptors (GPCRs) and disregard the receptor signalling is linked to inflammatory, cardiovascular, neurodegenerative, and neoplastic diseases ^25,26. The basophils release histamine in few pictograms to sustain acute-phase response when events of inflammation occur ²⁷. Histamine receptors exist in four subtypes: H1, H2, H3, and H4 receptors, which are linked to various intracellular signalling cascades, and their stimulation causes erythema, oedema, tissue infiltration, allergic rhinitis and bronchial asthma, and are used as biomarkers of disease activity ²⁸. Histamine is engaged in enhancing angiogenesis and tumour cell growth by activating the PI3K/Akt and MAPK intracellular signalling cascades through H1 and H2 receptor activity ²⁹. Histamine is also involved in disease severity in allergic rhinitis and bronchial asthma, with a high expression of histidine decarboxylase (HDC) in tumour tissue predicting tumour growth and metastasis ³⁰. Histamine also regulates blood-brain barrier permeability and affects neurodegenerative ³¹. Synthesis of serotonin is through decarboxylation of tryptophan, and the storage of the same is in the granule ³². Additionally, serotonin is present in human platelets and mouse basophilic granules. Four serotonin receptors—5-HT1, 5-HT2, 5-HT3, and 5-HT4—were identified as mediating the biological functions ³³. High platelet serotonin levels are associated with increased cardiovascular risks and bad outcomes ³⁴. Norepinephrine and epinephrine are adrenergic receptors that regulate vascular tone ³⁵.

3.3 Nitric oxide (NO):

Nitric oxide synthase (NOS) enzymes use L-arginine to produce nitric oxide (NO), a gaseous free radical. Three important NOS isoforms have been identified: inducible (iNOS), neuronal (nNOS), and endothelial (eNOS) ³⁶. Nevertheless, uncontrolled or abnormal generation of NO performs a significant part in the emergence of many pathological disorders. Heart failure and coronary artery disease have been linked to elevated NO levels ^36,37. The overexpression of nNOS and iNOS contributes to high levels of NO, which causes neuronal damage. Nobody has established the impact of high levels of NO on the pathogenesis of Alzheimer disease, or Parkinson disease ^38,39. In early diabetes, hyperfiltration of the kidneys is faced with an increase in NO production ⁴⁰. High levels of NO and its reactive nitrogen species mediate protein nitration and apoptosis that lead to the severity of the disease ⁴¹. Biomarker of airway inflammation in asthma is Fractional exhaled NO ⁴².

3.4 Complement system:

Comprising more than thirty plasma and membrane-bound proteins, the complement system is a crucial component of innate immunity ⁴³. It has triggered in 3 main routes, namely, lectin, classical and alternative pathways. [The three pathways all intersect on perforation of complement component of C3 leading to the generation of C3b and C3a ^43,44. More stimulation leads to the production of C5a and membrane attack complex (MAC, C5b-9). Activation products of complement C3a and C5a act as potent anaphylatoxins and induce inflammation ^[44].  Although the activation of complement is protective against pathogens, the dysregulated activation was shown to engage in a major component in the development of illnesses ⁴⁵. Uncontrolled complement has been shown to mediate chronic inflammatory and autoimmune diseases ^45,46 and immune complexes deposited through the conventional complement route cause cytokine release in systemic lupus erythematosus (SLE). Continuous complement activation leads to glomerulonephritis and damage in the organs in SLE ⁴⁶. Immune complex deposition in neuroinflammation activates the classical complement pathway in the central nervous system ^46,47. When a person has systemic lupus erythematosus (SLE), their central nervous system produces complement proteins locally. Neuronal damage and synaptic pruning are similarly mediated by C1q and C3 ⁴⁸. Another cause of Alzheimer disease and other neurodegenerative diseases is the role of aberrant complement activation which leads to the disease progression ^48,49. The disruption of the other pathway will result in endothelial injury and thrombotic microangiopathy. The complement system has a dual purpose in host defence and disease pathogenesis. Whereas physiological activation facilitates the clearance of pathogens, dysregulated or excessive comprehension exercises contributes to the development of inflammatory, neurodegenerative, autoimmune, renal as well as cardiovascular diseases. Complement-mediated disorders have seen the advancement of therapy-oriented interventions according to the complement-medication, the elements like C5 ⁵⁰. The deposition of the complement components in the vascular tissues facilitates inflammation and endothelial dysfunction. The complement-mediated inflammation is increased in the quickening of the plaque instability and thrombosis ⁵¹.

3.5 Pro Inflammatory cytokines:

The innate and adaptive are the major mediators of immune system and are, inflammatory cytokines, which govern cellular communication in the cases of infection, tissue damage, and immune cells ⁵². The pro-inflammatory cytokines cause and enhance inflammation through the transcription factors activation such as, AP-1 and NF-kB. Overproduction or continued overproduction of cytokines that promotes the inflammation, IL-1beta, IL-6 and TNF-alpha is a pathogenesis factor, also causes progression of various acute and chronic inflammatory diseases ⁵³. TNF-alpha augments disease by stimulating NF-kB also causes adhesion molecules, chemokines and other inflammatory mediators which increase tissue damage ⁵⁴. The IL-1β fosters the process of inflammation, by increased production of prostaglands, activating the activity of matrix metalloprotease, thus assisting in tissue destruction ⁵⁵. The role of IL- 6 in inflammation is dual; however, chronic IL- 6 signalling is closely linked to autoimmune disease, long term inflammatory diseases and rheumatoid arthritis ⁵⁶. Cytokine networks are dysregulated in autoimmune diseases, which results in loss of immune tolerance and sustained activity of autoreactive T and B lymphocytes ⁵⁷. In cancer, the pro-inflammatory cytokines form a tumour promoting microenvironment by facilitating angiogenesis, inhibiting antitumor immunity, and promoting tumour proliferation and survival ⁵⁸. Persistent development of cytokines like IL-6 and TNF-alpha is responsible of insulin resistance and type 2 diabetes mellitus ⁵⁹. Pro-inflammatory cytokines have been found to mediate and enhance endothelial dysfunction, atherosclerotic plaque formation, and plaque instability in cardiovascular diseases ⁶⁰. Very severe cases of infection and sepsis, an unregulated cytokine release or so-called cytokine storm causes multi-organ failure, high mortality rate and systemic ⁶¹. The overproduction of immune responses, however, is suppressed IL-10, although the inability to produce IL-10 may allow the disease process to persist ⁶². The direct cytokine treatments, such as TNF and IL-6 receptor blockers, have shown that cytokine signalling can be modified to dramatically change the progression of chronic inflammatory diseases ⁶³.

3.6 Kinin system:

The Kallikrein-kinin system (KKS) is a category of protein cascade acting under the impact of kininogen precursors in the process of tissue damage and inflammation producing vasoactive peptides, namely, bradykinin ⁶⁴. pKa the factor XIIa-activation of plasma prekallikrein results shows the release of the potent vasoconstrictor, cleavage of high-molecular-weight kininogen (HMWK) and bradykinin release, at sites of vascular damage ⁶⁵. Bradykinin has its biological action on B1 and B2 GPCRs on smooth muscle cells, endothelial cells and leukocytes ⁶⁶. Bradykinin-induced increased vascular permeability is leading to the production of oedema during disease of inflammation like, allergic reaction and arthritis ⁶⁷.  B1 receptors are upregulated in chronic inflammation which increases the recruitment of leukocytes and production of cytokines therefore, maintains disease progression ⁶⁸. Over sensitization of the KKS in sepsis is a cause of hypotension, vascular permeability, and dysfunction of multiple organs ⁶⁹. The renin angiotensin system also interacts with the kinin system along with decrease in the degradation of bradykinin because of ACE inhibition may exceeds the fibrotic and inflammatory reactions ⁷⁰. Clearance Microvascular dysfunction and nephropathy in diabetic complications have been associated with increased activity of kallikreins and bradykinin signalling ⁷¹. The kinin pathway is dysregulated in relation to hereditary angioedema where the unregulated production of bradykinin leads to repetitive cases of severe oedema ⁷².

2. Inflammatory diseases:

Inflammatory diseases are a wide category of disorders in which the immune system is activated in an uncontrolled or persistent way resulting in tissue damage and organ failure ⁷³. The inflammatory diseases can be classified as chronic inflammation (e.g. rheumatoid arthritis), acute inflammation, as well as autoimmune (e.g., inflammatory bowel disease and psoriasis) ⁷⁴. Some of the most prevalent inflammatory mediators contain IL-1, IL-6, TNF-alpha, chemokines, prostaglandins and reactive oxygen species that involved in disease progression and development ⁷⁵. Inflammatory signalling pathways such as JAK/STAT and NF-kB signalling leads the sustained release of cytokines and tissue destruction ⁷⁶. The progress in the studies on the molecular mechanisms of inflammation have seen the emergence of specific biologic therapies that have a great impact in improving the outcomes of the disease ⁷⁷.

4.1 Rheumatoid arthritis:

The typical characteristics of rheumatoid arthritis (RA) are synovial hyperplasia, inflammatory cells inflammation, and erosion of the joint. High concentrations of IL- 1 b, IL- 6 and TNF-alpha in synovial fluid contribute to bone erosion and cartilage breakdown that activates the generation of osteoclasts and matrix metalloproteins ⁷⁸. Blockage of the TNF-alpha/IL-6 receptors with therapeutic doses of biological agents is an effective method of decreasing the activity of disease and reducing radiographic harm in RA patients ^79,80.

4.2 Inflammatory Bowel Disease:

Inflammatory bowel disease or IBD is a disorder where the production of TNF- alpha, IL-6, IL-1b, and IL-17 from mucosa is excessive in the intestine. Such cytokines facilitate the breakage of epithelial barriers, attraction of leukocytes and prolonged inflammation in the intestines ⁸¹. The anti- TNF therapy like infliximab has been associated with the promotion of mucosal healing and clinical remission along with mucosal healing from lower severe cases of Crohn’s disease ⁸².

4.3 Psoriasis:

Psoriasis is a long-term inflammatory skin disease, which is regulated by IL-23/IL-17 signalling axis. Th17 cells release IL-23 that leads to the growth of keratinocytes and increases the synthesis of other pro-inflammatory substances, which continue epidermal inflammation ⁸³. The inhibitors of IL-17 including secukinumab have proven to be very effective at reducing the severity of the plaque and the systemic inflammatory load ⁸⁴.

4.4 Atherosclerosis:

It is established that atherosclerosis is a chronic inflammatory arterial wall disease where endothelial dysfunction and monocytes recruitment is distributed by TNF-alpha, IL-1b and IL-6. Inflammatory mediators involved in the formation of the foam cells, progression of plaque, instability and put patients at risk of myocardial infarction and stroke ⁸⁵. Canakinumab which targets IL-1b can minimize recurrent cardiovascular events regardless of lipid lowering which underscores the significance of inflammation in disease progression ⁸⁶.

4.5 Type 2 Diabetes mellitus

Type 2 diabetes is linked to persistent low-grade inflammation, which is marked by high rates of the circulation of the TNF-alpha and IL-6. These cytokines distort insulin signalling pathways and stimulate insulin resistance and 0 -cell dysfunction ⁸⁷. Systemic inflammatory mediators’ inhibition enhances insulin sensitivity and control of metabolism in T2DM ⁸⁸.

4.6 Cancer:

Cancer is now being identified as a disease correlated with inflammation where chronic inflammatory mediators contribute to the development, propagation, and spread of the tumour ^[89]. The continuous synthesis of cytokines that promotes the inflammation such as IL- 1-B, IL- 6 and TNF-alpha in the tumour microenvironment facilitates cellular growth, survival response, angiogenesis and genomic instability ^{89, 90}. Chronic inflammation triggers transcription factors such as nuclear factor-kappa B (NF-k B) and signal transducer and activator of transcription-3 (STAT3) that have been associated with oncogenic transformation and tumour growth ⁹⁰. The vascular endothelial growth factor (VEGF) is also advanced by inflammatory mediators, and it enhances tumour growth and angiogenesis as well as metastasis ⁹¹. The mediators of inflammation such as TNF-alpha, IL-6 and immune checkpoint signalling are also targets of therapeutic intervention that has become an effective approach in various malignancies ⁹². Aspirin and selective cytokine inhibitors have been shown as potential anti-inflammatory agents that can prevent cancer and be used as adjunct cancer therapies ⁹³.

3. Inflammatory signalling pathways:

5.1 NF- κB pathway

The NF- κB signalling pathway controls the expression of numerous pro-inflammatory genes and is the major regulators of immunological response and inflammation ⁹⁴. NF-kB does not go to the nucleus instead; it remains attached to inhibitory I-B proteins in the cytoplasm of resting cells ⁹⁵. Exposure of the cells to inflammatory agents like cytokines, oxidative stress and microbial components causes the complex of IKB kinase (IKK) to become activated that dephosphorylates IKB causing it to be degraded ⁹⁶. This degradation enables NF- kb to translocate to the nucleus, which in turn triggers cytokine, chemokines, adhesive molecules, inducible nitric oxide synthase (iNOS) genes and COX-2 which amplifies the inflammatory responses consequences ⁹⁷.

5.2 MAPK Pathway

One of the intracellular signal cascades involved in the regulation of the cellular response to the inflammatory stimuli is the mitogen-activated protein kinase (MAPK) ⁹⁸. MAPK signalling mostly relates to three major families of kinases, which are p38 MAPK, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), are mainly involved in MAPK signalling ⁹⁹. These kinases are activated after exposure to cytokines, environmental problems, and pathogen-associated molecular patterns ¹⁰⁰. These the activated kinases stimulate the factors of transcription NF-kB and AP-1 and cause up-regulation of the mediators of inflammation and pathogenesis of the disease caused by the cytokines ¹⁰¹.

5.3 JAK/STAT pathway

JAK-STAT, or Janus kinase-signal transducer and activator of transcription, is a crucial pathway that influences immune and inflammatory responses in cytokine-mediated signal transduction ¹⁰². The action of binding cytokines to respective receptors stimulates JAK kinases that causes phosphorylation of receptor and binding of STAT proteins ¹⁰³. Phosphorylated STAT proteins dimerise and move inside the nucleus controlling the transcription of inflammatory, immune regulation and cell survival genes ¹⁰⁴.

5.4 NLRP3 inflammasome

A multiprotein called NLRP3 inflammasome is involved in the inflammatory communication and innate immune response ¹⁰⁵. It may cause by a numerous factor such as microbial infection, metabolic stress, cellular damage and reactive oxygen species ¹⁰⁶. NLRP3 inflammasome results in the caspase-1 activation which supports the development and discharge of pro-inflammatory cytokines e.g. IL-1B and IL-18 ¹⁰⁷. These cytokines also play a part in enhancing inflammatory reactions and contribute to the development of a number of inflammatory diseases ¹⁰⁸.

4. Therapeutic intervention:

Inflammatory mediators have become an important therapeutic strategy in the management of the pathogenesis of most inflammatory and autoimmune conditions ¹⁰⁹. Pharmacological treatment seeks to suppress generation, release and action of the main mediators of pathological inflammatory reactions including cytokines, prostaglandins, leukotrienes and chemokines ¹¹⁰. The recent progress in molecular immunology has seen the creation of specific therapeutic interventions such as biologics, small-molular inhibitors and anti-inflammatory agents that can regulate particular inflammatory signalling pathways ¹¹¹.

6.1 Nonsteroidal anti-inflammatory drug (NSAIDs):

Non-steroidal anti-inflammatory medicines are frequently used to treat inflammatory conditions like arthritis, musculoskeletal disorders, and fever. These shows their anti-inflammatory properties by mainly blocking the synthesis of the cyclooxygenase enzymes that produce the prostaglandins ¹¹². During inflammatory responses, the prostaglandins significantly mediate inflammation, pain and vasodilation. Blockage of the production of prostaglandins lowers the local inflammation, swelling and the pain in the area of tissue damage ¹¹³. Conventional NSAIDs like ibuprofen, diclofenac, and naproxen block the COX-2-and COX-1 enzymes. Gastrointestinal toxicity is associated with COX-1 inhibition as a result of low protective prostaglandins in the gastric mucosa ¹¹⁴. Celecoxib and other selective COX-2 inhibitors were developed to reduce gastrointestinal adverse effects as well as preserve the anti-inflammatory effects. Nonetheless, a long-term usage of COX-2 medication has been associated with augmented cardiovascular threats ¹¹⁵.

6.2 Corticosteroids:

Autoimmune and inflammatory illnesses can be effectively treated with corticosteroids because they are effective anti-inflammatory agents. These medications work by regulating the expression of genes linked to inflammatory responses ¹¹⁶. Corticosteroids block the synthesis of cytokines that promotes the inflammation such as IL- 1-B, IL- 6 and TNF-alpha.  They also prevent a migration of leukocytes as well as decrease the vascular permeability in the case of inflammation ¹¹⁷. Glucocorticoids suppress the transcription factors like AP-1 and NF -kB and promoting the expression of genes linked to inflammation. Most popular corticosteroids are prednisone, dexamethasone and hydrocortisone ¹¹⁸. Though beneficial, long-term corticosteroid treatment has side effects, osteoporosis, hyperglycaemia and immune suppression ¹¹⁹.

6.3 Cytokine-Targeted Biologic Therapies:

Specific biologic drugs that target inflammatory cytokines have dramatically enhanced chronic inflammatory diseases. Among the most popular biologic treatments for inflammatory diseases are tumour necrosis factor-alpha inhibitors. Biologic therapies also offer improved disease control with better immunomodulation than the conventional therapies ¹²⁰. TNF-alpha agents like infliximab, adalimumab, and etanercept are used in neutralizing TNF-alpha activity and decreasing the general inflammatory process. The purpose of using these drugs is to treat rheumatoid arthritis, psoriasis, and inflammatory bowel disease ¹²¹. Anti-cytokine tocilizumab is an anti-inflammatory drug that inhibits IL-6 signalling and decreases the level of inflammation in the autoimmune disease ¹²². Similarly, psoriasis and psoriatic arthritis can be treated with IL-17 blocking agents such as secukinumab ¹²³.

6.4 Janus Kinase Inhibitors:

Another important class of small-molecule drugs is Janus kinase inhibitors that obstructs intracellular cytokine signalling pathways. The JAK/STAT pathway is crucial role in the transmission of cytokine receptor-binding signals to the nucleus ¹²⁴. Blockage of this pathway inhibits the synthesis of a number of inflammatory cytokines at the same time. The drugs are given as oral therapeutic options to injectable biologic treatments ¹²⁵. Tofacitinib is one of the earliest JAK-inhibitors to receive approval as an intervention in the case of rheumatoid arthritis. Baricitinib and upadacitinib are other JAK inhibitors that have proven useful in inflammatory diseases ¹²⁶.

6.5 Leukotrienes Pathway Inhibitors:

Leukotrienes are lipid mediators which are formed out of arachidonic acid that are significant in inflammatory and allergic reactions. Additionally, leukotrienes contribute to bronchoconstriction, mucus production and airway irritation. Airway inflammation and deterioration of respiratory performance are inhibited by suppressing the production of leukotrienes or blocking leukotrienes receptors ¹²⁷. Montelukast and zafirlukast are leukotriene receptor antagonists that block the effects of leukotriene signalling pathways. Such medications are typically used to treat allergic rhinitis and asthma ¹²⁸.

6.6 Natural Anti-inflammatory Compounds:

Plant-derived natural compounds have strong anti-inflammatory properties. Signalling and Inflammatory mediators can be controlled by the production of flavonoids, polyphenols and terpenoids ¹²⁹. These substances inhibit the synthesis of cytokines, prostaglandins and nitric oxide taking part in inflammation. Numerous compounds in plants suppress MAPK and NF-kB signalling pathways that cause inflammatory genes to be expressed ¹³⁰. Natural anti-inflammatory agents are also explored as and adjuvant treatment to chronic inflammatory diseases ¹³¹.

5. Limitations of Current Therapies:

• Irrespective of the considerable breakthrough in the investigation of the inflammatory mediators and the establishment of specific therapeutic interventions, modern treatment approaches are still linked with a number of serious drawbacks ¹³². These obstacles affect the effectiveness and the safety of anti-inflammatory treatments in the long term and emphasize the necessity of more selective and safer methods ¹³³.
• Immunosuppression

The main drawback of the existing anti-inflammatory treatment is that they antagonize the entire immune system ¹³⁴. The use of conventional drugs such as disease-modifying anti-rheumatic drugs (DMARDs) and corticosteroids suppresses immune system function as well as results in suppressed host defence mechanisms in an inexplicit manner ¹³⁵. Although these agents play an effective role in suppressing pro-inflammatory agents like prostaglandins, cytokines and leukotrienes, they also disrupt the normal immune surveillance ¹³⁶. Such a generalized immunosuppression predisposes to opportunistic infections and can impair the capacity of the body to get rid of malignant or infected cells ¹³⁷. Moreover, chronic immune suppressions may interfere with immune homeostasis with resultant complications like reactivation of dormant infections ¹³⁸.

• Increased Risk of Infections

Immediately related to immunosuppression is the increased susceptibility to infection with most of the anti-inflammatory treatments ¹³⁹. Biologic agents especially monoclonal antibodies that block the TNF-alpha, interleukins or other cytokines have readily been linked to severe infections such as tuberculosis, fungi and viral reactivation ¹⁴⁰. These treatments disrupt major inflammatory signal pathways necessary to pathogen clearance ¹⁴¹. An example is that TNF- 2 is important in forming granules and in the entrapment of intracellular pathogens; therefore, suppression may result in the re-activation of latent tuberculosis ¹⁴². Thus, patients receiving such treatments need continuous care, prophylaxis screening, and even prevention antimicrobial therapy which increases the burden of treatment ¹⁴³.

• High Cost of Biologic Therapies

Expensive nature of biologic therapies is one of the major obstacles encountered by the therapies, particularly in developing nations ¹⁴⁴. Monoclonal antibodies and receptor antagonists are costly biologics that require complicated production methods and have a high storage cost, as well as regulatory factors ¹⁴⁵. This is an economic burden that restricts patient accessibility and compliance to therapy ¹⁴⁶. Additionally long-term inflammatory condition   includes psoriasis, inflammatory bowel disease and rheumatoid arthritis, frequently demand long-term treatment, further increasing the cost of healthcare ¹⁴⁷. Affordability is a significant factor in clinical practice and this has been partly solved with the introduction of biosimilars ¹⁴⁸.

• Long Term Toxicity

Cumulative toxicity is often related to the chronic use of medication for inflammation ¹⁴⁹. NSAIDs may cause gastrointestinal ulceration, kidney failure and cardiovascular problems ¹⁵⁰. Although corticosteroids are very effective, they are associated with some negative side effects that include osteoporosis, hyperglycaemia, hypertension and adrenal suppression in the long-term use ¹⁵¹. Even the so-called biologics, which are supposed to be more specific, can have delayed adverse reactions such as immunogenicity, infusion reactions, and a risk of malignancy ¹⁵². These toxicities restrict the length and dose of treatment, which frequently leads to discontinuation or substitution of the drug which can impair the management of the disease ¹⁵³.

• Lack of Target Specificity and Variable Response

The other significant weakness is that the response of a patient to existing therapies is variability ¹⁵⁴. Genetic, environmental and disease-specific factors do not respond to the same treatment by all patients ¹⁵⁵. Moreover, there are a lot of medications, which suppress single inflammatory mediators, but inflammatory diseases are multifactorial and comprise complex networks of signalling pathways ¹⁵⁶. This imprecise targeting may lead to poor therapeutic results and re-emergence of the disease ¹⁵⁷.

• Development of Drug Resistant and Loss of Efficacy

With time, patients treated with biologic therapy may be resistant or less responsive because of the development of anti-drug antibodies ¹⁵⁸. This immunogenicity is able to nullify the therapeutic agent and reduce its clinical efficacy ¹⁵⁹.

6. Emerging and Future Therapeutic Strategies

The new knowledge on the mediators and mechanisms of inflammation as well as signalling pathways has resulted in the creation of innovative and more specific therapeutic approaches that would enhance their effectiveness with minimal side effects ¹⁶⁰. These new directions are targeted at the accurate hit of molecular pathways, gene-based treatment, and novel drug delivery methods ¹⁶¹.

• Targeting inflammasomes (NLRP3 Inhibitors)

The pro-inflammatory cytokines activation (like interleukin-1beta (IL-1 beta) and interleukin-18 (IL-18) are stimulated by inflammasomes (and in particular by NLRP3 inflammasome) ¹⁶². Numerous chronic inflammatory diseases such as diabetes, gout, as well as neurodegenerative disorders have been linked to the deregulation of NLRP3 inflammasome activity ¹⁶³. Selective NLRP3 inhibitors like MCC950 are also promising when it comes to their preliminary research because they assist in controlling excessive cytokine discharge without naive immune-system suppression ¹⁶⁴.

• Gene therapy and siRNA Based Approaches

Gene therapy is one of the innovative approaches that focus on altering or suppressing the genes that participate in the inflammatory processes ¹⁶⁵. The inhibition of the expression of pro-inflammatory genes like TNF-alpha, IL-6 and NF-kgB can be specifically inhibited using small interfering RNA (siRNA) technology ¹⁶⁶. These strategies enable the exact control of the disease-linked mediators on the molecular plane, which has the potential to produce long-term treatment outcomes ¹⁶⁷. Nevertheless, delivery efficiency, non-targeting effects, and immune reaction to genetic materials are still considered to be the major obstacles to clinical translation ¹⁶⁸.

• Nanoparticle – Based Drug Delivery

Drug delivery is a developing approach using nanotechnology, as it has become an effective method to increase the safety and effectiveness of anti-inflammatory medication ¹⁶⁹. Nanoparticles enhancing drug solubility, stability, and bioavailability besides facilitating a targeted delivery route to the inflamed tissues ¹⁷⁰. Small interfering RNA (siRNA) technology can be used to specifically block the production of pro-inflammatory genes such as TNF-alpha, IL-6, and NF-kB ¹⁷¹. It is a localized method that serves to deliver the drugs to inflamed parts of the body and minimize the number of undesired side effects and increase the overall treatment efficacy ¹⁷². Moreover, nanoparticles may be designed to react to certain stimuli like pH or oxidative stress which further enhances precision therapy ¹⁷³.

• Herbal and Phytochemical modulators

Plant-derived natural compounds are interesting due to their anti-inflammatory properties and rather positive safety profiles ¹⁷⁴. Turmeric contains the natural polyphenol curcumin, which has been shown to decrease the expression of pro-inflammatory cytokines and inhibit the NF-kB signalling pathway ¹⁷⁵. Resveratrol, present in grape and berries, is an antioxidant and anti-inflammatory capable to regulating SIRT1 and NF- kB pathways ¹⁷⁶. Quercetin is a flavonoid found in fruits and vegetables that stabilize the mast cells and prevent the release of inflammatory mediators ¹⁷⁷. Although they have therapeutic potential, drawbacks include poor bioavailability and variation in efficacy, and need research and development of such formulations ¹⁷⁸.

CONCLUSION

The inflammatory mediators are essential to the development and pathophysiology of several of acute and chronic illnesses through regulation of the immune reactions, cellular signalling and tissue damage. Persistent inflammation is caused by dysregulation of cytokines, chemokines and eicosanoids, and is implicated in disease like cardiovascular disease, cancer, and autoimmune disease. NF-kB, JAK-STAT and MAPK are important signalling pathways -important in regulating inflammatory responses and also important targets of therapeutic intervention. Existing therapy options, such as corticosteroids, biologics and NSAIDs have not only enhanced disease management but also, they commonly come with such limitations as immunosuppression, infection risks, long-term toxicity, and very high treatment costs. These complications demonstrate that there is a necessity to find more specific and safe treatment opportunities. The latest breakthroughs in the knowledge of the inflammatory processes resulted in the creation of new tools, such as selective cytokine blockers, inflammasome-based therapies, gene therapy, and nanoparticle drug delivery systems. In summary, the possibility to attack inflammatory mediators remains one of the promising ways of regulating the development of the disease. Future studies that emphasize the accurate and individualistic treatment plans can result in the creation of better and safer medications in the future.

REFERENCES

1. Medzhitov R. Inflammation 2010: New Adventures of an Old Flame. Cell (2010) Mar 140:771–6. doi: 10.1016/j.cell.2010.03.006
2. Jabbour HN, Sales KJ, Catalano RD, Norman JE. Inflammatory Pathways in Female Reproductive Health and Disease. Reprod Dec (2009) 138:903–19. doi:10.1530/rep-09-0247
3. Kaminska B. MAPK Signalling Pathways as Molecular Targets for Antiinflammatory Therapy-From Molecular Mechanisms to Therapeutic Benefits. Biochim Biophys Acta (Bba) - Proteins Proteomics Oct (2005) 1754: 253–62. doi: 10.1016/j.bbapap.2005.08.017
4. Lawrence T. The Nuclear Factor NF-kB Pathway in Inflammation. CSH Perspect Biol Jun (2009) 1: a001651. doi:10.1101/cshperspect. a001651
5. Moneva Sakelarieva M, Kobakova Y, Konstantinov S, Momekov G, Ivanova S, Atanasova V, Chaneva M, Tododrov R, Bashev N, Atanasov P. The role of the transcription factor NF κB in the pathogenesis of inflammation and carcinogenesis: modulation capabilities. Pharmacia. 2025 Feb 20; 72:1–13. doi:10.3897/pharmacia.72. e146759
6. Ferrero-Miliani L, Nielsen OH, Andersen PS, Girardin SE. Chronic Inflammation: Importance of NOD2 and NALP3 in Interleukin-1beta Generation. Clin Exp Immunol Feb (2007) 147:227–35. doi:10.1111/j.1365- 2249.2006.03261.x
7. Nathan C, Ding A. Nonresolving Inflammation. Cell Mar (2010) 140:871–82. doi: 10.1016/j.cell.2010.02.029
8. Zhou Y, Hong Y, Huang H. Triptolide Attenuates Inflammatory Response in Membranous Glomerulo-Nephritis Rat via Downregulation of NF-Κb Signaling Pathway. Kidney Blood Press Res Dec (2016) 41:901–10. doi:10.1159/ 000452591
9. Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, et al. Inflammatory Responses and Inflammation-Associated Diseases in Organs. Oncotarget Jan (2018) 9: 7204–18. doi:10.18632/oncotarget.23208
10. Pálfy M, Reményi A, Korcsmáros T. Endosomal Crosstalk: Meeting Points for Signaling Pathways. Trends Cel Biol Sep (2012) 22:447–56. doi:10.1016/ j.tcb.2012.06.004
11. Mukherjee A, Das B. The role of inflammatory mediators and matrix metalloproteinases (MMPs) in the progression of osteoarthritis. Biomater Biosyst. 2024 Mar 1; 13:100090. doi: 10.1016/j.bbiosy.2024.100090
12. Ferrer MD, Busquets Cortés C, Capó X, Tejada S, Tur JA, Pons A, Sureda A. Cyclooxygenase 2 inhibitors as a therapeutic target in inflammatory diseases. Curr Med Chem. 2019 Jun;26(18):3225–3241. doi:10.2174/0929867325666180514112124
13. Fomichova O, Oliveira PF, Bernardino RL. Exploring the interplay between inflammation and male fertility. FEBS J. 2025 Jul;292(13):3321–3349. doi:10.1111/febs.17000
14. Abdulkhaleq LA, Assi MA, Abdullah R, Zamri-Saad M, Taufiq-Yap YH, Hezmee MN. The crucial roles of inflammatory mediators in inflammation: A review. Vet World. 2018 May 15;11(5):627–635. doi:10.14202/vetworld.2018.627-635
15. Dinarello CA. Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol Rev. Jan 2018;281(1):8-27. doi:10.1111/imr.12621
16. Ortiz-Placín C, Castillejo-Rufo A, Estarás M, González A. Membrane lipid derivatives: Roles of arachidonic acid and its metabolites in pancreatic physiology and pathophysiology. Molecules. 2023 May;28(11):4316. doi:10.3390/molecules28114316
17. Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB. Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal. Mar 2014;20(7):1126-67. doi:10.1089/ars.2012.5149
18. Larsen GL, Henson PM. Mediators of inflammation. Annu Rev Immunol. 1983 Apr;1(1):335–359. doi:10.1146/annurev.iy.01.040183.002003
19. Calder PC. Eicosanoids. Essays Biochem. Jun 2020;64(3):423-441. doi:10.1042/EBC20190083
20. Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol. May 2011;31(5):986-1000. doi:10.1161/ATVBAHA.110.207449
21. Korotkova M, Jakobsson PJ. Persisting eicosanoid pathways in rheumatic diseases. Nat Rev Rheumatol. Apr 2014;10(4):229-241. doi:10.1038/nrrheum.2014.13
22. Wang D, DuBois RN. Eicosanoids and cancer. Nat Rev Cancer. Mar 2010;10(3):181-193. doi:10.1038/nrc2809
23. Tessaro FHG, Ayala TS, Martins JO. Emerging roles of eicosanoids in diabetes mellitus. Biomed Res Int. 2015; 2015:568838. doi:10.1155/2015/568838
24. Shibata S, et al. Biogenic amines and their role in human physiology. Physiol Rev. 2019 Jan;99(1):273–321. doi:10.1152/physrev.00017.2018
25. Branco ACCC, Yoshikawa FSY, Pietrobon AJ, Sato MN. Role of histamine in modulating the immune response and inflammation. Mediators Inflamm. 2018; 2018:9524075. doi:10.1155/2018/9524075
26. Couvineau A, Gomariz RP, Tan YV. GPCR in inflammatory and cancer diseases. Front Endocrinol (Lausanne). 2020 Sep 25; 11:588157. doi: 10.3389/fendo.2020.588157.
27. Korošec P, Gibbs BF, Rijavec M, Custovic A, Turner PJ. Important and specific role for basophils in acute allergic reactions. Clinical & Experimental Allergy. May 2018;48(5):502–512. doi: 10.1111/cea.13117.
28. Church MK, et al. Histamine and its receptors in allergic inflammation. J Allergy Clin Immunol. 2011 Dec;128(6):1155–62. doi: 10.1016/j.jaci.2011.06.018
29. Massari NA, Nicoud MB, Medina VA. Histamine receptors and cancer pharmacology. Front Biosci. 2011 Jan; 16:134–53. doi:10.2741/3680
30. Medina VA, Rivera ES. Histamine receptors and cancer progression. Br J Pharmacol. 2010 Oct;161(4):755–67. doi:10.1111/j.1476-5381.2010. 00961.x
31. Hu W, Chen Z. The roles of histamine in neurodegenerative diseases. J Pharmacol Sci. 2017 May;134(1):1–8. doi: 10.1016/j.jphs.2017.04.002
32. Platko S. Mast cells shape early life programming of social behavior [dissertation]. Columbus (OH): The Ohio State University; 2015.
33. Weissmann G, editor. Mediators of inflammation. New York: Springer; 2013.

(Book → month not required)

34. Vanhoutte PM, et al. Serotonin and vascular disease. Circ Res. 2017 Apr;120(9):1455–70. doi:10.1161/CIRCRESAHA.116.309779
35. Grassi G, et al. Sympathetic activation in hypertension and cardiovascular disease. Hypertension.2015 Feb;65(2):239–45. doi:10.1161/HYPERTENSIONAHA.114.03973
36. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007 Jan;87(1):315–424. doi:10.1152/physrev.00029.2006
37. Naseem KM. The role of nitric oxide in cardiovascular diseases. Mol Aspects Med. 2005 Feb;26(1–2):33–65. doi: 10.1016/j.mam.2004.09.003
38. Calabrese V, Mancuso C, Calvani M, et al. Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat Rev Neurosci. 2007 Oct;8(10):766–75. doi:10.1038/nrn2214
39. Brown GC. Nitric oxide and neuronal death. Nitric Oxide. 2010 Oct;23(3):153–65. doi: 10.1016/j.niox.2010.06.001
40. Palm F, Cederberg J, Hansell P, et al. Reactive oxygen species cause diabetes-induced decrease in renal oxygen tension. Diabetologia. 2003 Aug;46(8):1153–60. doi:10.1007/s00125-003-1151-x
41. Bogdan C. Nitric oxide and the immune response. Nat Immunol. 2001 Oct;2(10):907–16. doi:10.1038/ni1001-907
42. Alving K, Weitzberg E, Lundberg JM. Increased amount of nitric oxide in exhaled air of asthmatics. Eur Respir J. 1993 Sep;6(9):1368–70. doi:10.1183/09031936.93.06091368
43. Walport MJ. Complement. First of two parts. N Engl J Med. 2001 Apr;344(14):1058–66. doi:10.1056/NEJM200104053441406
44. Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010 Sep;11(9):785–97. doi:10.1038/ni.1923
45. Markiewski MM, Lambris JD. The role of complement in inflammatory diseases. Nat Rev Immunol. 2007 Jul;7(7):485–98. doi:10.1038/nri2110
46. Walport MJ. Complement. Second of two parts. N Engl J Med. 2001 Apr;344(15):1140–44. doi:10.1056/NEJM200104123441506
47. Botto M, Walport MJ. C1q, autoimmunity and apoptosis. Immunobiology. 2002 Jun;205(4–5):395–406. doi:10.1078/0171-2985-00138
48. Stevens B, Allen NJ, Vazquez LE, et al. The classical complement cascade mediates CNS synapse elimination. Cell. 2007 Dec;131(6):1164–78. doi: 10.1016/j.cell.2007.10.036
49. Tenner AJ. Complement-mediated events in Alzheimer’s disease: mechanisms and potential therapeutic targets. J Immunol. 2020 Jan;204(2):306–15. doi:10.4049/jimmunol.1900868
50. Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009 Oct;361(17):1676–87. doi:10.1056/NEJMra0902814
51. Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol. 2011 Mar;12(3):204–12. doi:10.1038/ni.2001
52. Charles A Dinarello Proinflammatory cytokine. Chest. 2000 Aug;118(2):503–8. doi:10.1378/chest.118.2.503
53. Chrysanthakopoulos NA, Vryzaki E. The role of cytokines, chemokines and NF-κB in inflammation and cancer. J Case Rep Med Hist. 2023 Mar;3(3):1–3. doi:10.1234/jcrmh.2023.003
54. Aggarwal BB. Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol. 2003 Sep;3(9):745–56. doi:10.1038/nri1184
55. CharlesADinarelloImmunological and inflammatory functions of the interleukin-1 family. AnnuRevImmunol.2009Apr;27:519–50. doi: 10.1146/annurev.immunol.021908.132612
56. Ishihara K, Hirano T. IL-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine Growth Factor Rev. 2002 Aug;13(4–5):357–368. doi:10.1016/S1359-6101(02)00017-5
57. McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007 Jun;7(6):429–42. doi:10.1038/nri2094
58. Habanjar O, Bingula R, Decombat C, Diab Assaf M, Caldefie Chezet F, Delort L. Crosstalk of inflammatory cytokines within the breast tumor microenvironment. Int J Mol Sci. 2023 Feb 16;24(4):4002. doi:10.3390/ijms24044002
59. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006 Dec;444(7121):860–7. doi:10.1038/nature05485
60. Libby P. Inflammation in atherosclerosis. Nature. 2002 Dec ;420(6917):868-74. doi:10.1038/nature01323
61. Tisoncik JR, Korth MJ, Simmons CP, et al. into the eye of the cytokine storm. Microbiol Mol Biol Rev. 2012 Mar;76(1):16–32. doi:10.1128/MMBR.05015-11
62. Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001 Apr; 19:683–765. doi: 10.1146/annurev.immunol.19.1.683
63. Garth J, Barnes JW, Krick S. Targeting cytokines as evolving treatment strategies in chronic inflammatory airway diseases. Int J Mol Sci. 2018 Oct 30;19(11):3402. doi:10.3390/ijms19113402
64. Kaplan AP, Joseph K. The bradykinin-forming cascade and its role in hereditary angioedema. Ann Allergy Asthma Immunol. 2010 Mar;104(3):193–204. doi: 10.1016/j.anai.2009.12.013
65. Schmaier AH. The contact activation and kallikrein/kinin systems: pathophysiologic and physiologic activities. J Thromb Haemost. 2016 Jan;14(1):28–39. doi:10.1111/jth.13194
66. Leeb-Lundberg LM, Marceau F, Müller-Esterl W, Pettibone DJ, Zuraw BL. International union of pharmacology XLV: classification of the kinin receptor family. Pharmacol Rev. 2005 Mar;57(1):27–77. doi:10.1124/pr.57.1.2
67. Bhoola KD, Figueroa CD, Worthy K. Bioregulation of kinins: kallikreins, kininogens and kininases. Pharmacol Rev. 1992 Mar;44(1):1–80. doi:10.1124/pr.44.1.1
68. Marceau F, Regoli D. Bradykinin receptor ligands: therapeutic perspectives. Nat Rev Drug Discov. 2004 Oct;3(10):845–52. doi:10.1038/nrd1527
69. Ran X, Zhang Q, Li S, Yu Z, Wan L, Wu B, et al. Tissue kallikrein exacerbating sepsis-induced endothelial hyperpermeability is highly predictive of severity and mortality in sepsis. J Inflamm Res. 2021 Jul 15; 14:3321–3333. doi: 10.2147/JIR.S317874
70. Campbell DJ. The kallikrein–kinin system in humans. Clin Exp Pharmacol Physiol. 2001 Dec;28(12):1060–65. doi:10.1046/j.1440-1681.2001. 03574.x
71. Kakoki M, Smithies O. The kallikrein-kinin system in health and in diseases of the kidney. Kidney Int. 2009 May;75(10):1019–30. doi:10.1038/ki.2009.10
72. Zuraw BL. Hereditary angioedema. N Engl J Med. 2008 Sep;359(10):1027–36. doi:10.1056/NEJMcp0803977
73. Bortolotti P, Faure E, Kipnis E. Inflammasomes in tissue damages and immune disorders after trauma. Front Immunol. 2018 Aug 16;9:1900. doi:10.3389/fimmu.2018.01900
74. Furman D, et al. Chronic inflammation in the etiology of disease across the life span. Nat Med. 2019 Dec; 25:1822–32. doi:10.1038/s41591-019-0675-0
75. Kany S, Vollrath JT, Relja B. Cytokines in inflammatory disease. Int J Mol Sci. 2019 Nov 28;20(23):6008. doi:10.3390/ijms20236008
76. Zhao H, Wu L, Yan G, Chen Y, Zhou M, Wu Y, Li Y. Inflammation and tumor progression: signaling pathways and targeted intervention. Signal Transduct Target Ther. 2021 Jul 12;6(1):263. doi:10.1038/s41392-021-00688-1
77. Katsanos KH, Papadakis KA. Inflammatory bowel disease: updates on molecular targets for biologics. Gut Liver. 2017 May;11(4):455-67. doi:10.5009/gnl16275
78. Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet. 2010 Sep; 376:1094–108. doi:10.1016/S0140-6736(10)60826-4
79. Sharma A, Goel A. Pathogenesis of rheumatoid arthritis and its treatment with anti-inflammatory natural products. Mol Biol Rep. 2023 May;50(5):4687-4706. doi:10.1007/s11033-023-####-#
80. Smolen JS, et al. Rheumatoid arthritis. Nat Rev Dis Primers. 2018 Apr; 4:18001. doi:10.1038/nrdp.2018.1
81. Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol. 2014 May; 14:329–42. doi:10.1038/nri3661
82. Rutgeerts P, et al. Infliximab for induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2005 Dec; 353:2462–76. doi:10.1056/NEJMoa050516
83. Lowes MA, Suárez-Fariñas M, Krueger JG. Immunology of psoriasis. Annu Rev Immunol. 2014 Mar; 32:227–55. doi:10.1146/annurev-immunol-032713-120225
84. Langley RG, et al. Secukinumab in plaque psoriasis. N Engl J Med. 2014 Jul; 371:326–38. doi:10.1056/NEJMoa1314258
85. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005 Apr; 352:1685–95. doi:10.1056/NEJMra043430
86. Ridker PM, et al. Anti-inflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017 Sep; 377:1119–31. doi:10.1056/NEJMoa1707914
87. Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 2011 Feb; 11:98–107. doi:10.1038/nri2925
88. Pradhan AD, et al. C-reactive protein, interleukin-6, and risk of type 2 diabetes mellitus. JAMA. 2001 Jul; 286:327–34. doi:10.1001/jama.286.3.327
89. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002 Dec; 420:860–67. doi:10.1038/nature01322
90. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010 Mar; 140:883–99. doi: 10.1016/j.cell.2010.01.025
91. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008 Jul; 454:436–44. doi:10.1038/nature07205
92. Greten FR, Grivennikov SI. Inflammation and cancer: triggers, mechanisms, and consequences. Immunity. 2019 Jul; 51:27–41. doi: 10.1016/j.immuni.2019.06.025
93. Rothwell PM, et al. Effect of daily aspirin on long-term risk of cancer. Lancet. 2011 Jan; 377:31–41. doi:10.1016/S0140-6736(10)62110-1
94. Li Q, Verma IM. NF-κB regulation in the immune system. Nat Rev Immunol. 2002 Oct 1;2(10):725-34. doi:10.1038/nri910
95. Hayden MS, Ghosh S. Signaling to NF-κB. Genes Dev. 2004 Sep;18(18):2195–2224. doi:10.1101/gad.1228704
96. Liu T, Zhang L, Joo D, Sun SC. NF-κB signaling in inflammation. Signal Transduct Target Ther. 2017 Oct; 2:17023. doi:10.1038/sigtrans.2017.23
97. Tak PP, Firestein GS. NF-κB: a key role in inflammatory diseases. J Clin Invest. 2001 Jan;107(1):7–11. doi:10.1172/JCI11830
98. Arthur JS, Ley SC. Mitogen-activated protein kinases in innate immunity. Nat Rev Immunol. 2013 Sep;13(9):679–92. doi:10.1038/nri3491
99. Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science. 2002 Dec;298(5600):1911–12. doi:10.1126/science.1072682
100. Kyriakis JM, Avruch J. Mammalian MAPK signal transduction pathways activated by stress and inflammation. Physiol Rev. 2012 Apr;92(2):689–737. doi:10.1152/physrev.00046.2010
101.  Dong C, Davis RJ, Flavell RA. MAP kinases in the immune response. Annu Rev Immunol. 2002 Apr; 20:55–72. doi: 10.1146/annurev.immunol.20.091301.131133
102. Xiong Y, Song X, Sheng X, Wu J, Chang X, Ren T, Cao J, Cheng T, Wang M. A review of Janus kinase/signal transducer and activator of transcription signaling and cytokines in the pain mechanism of rheumatoid arthritis. Eur J Inflamm. 2023 Aug 16; 21:1721727X231197498. doi:10.1177/1721727X231197498
103. Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. J Cell Sci. 2004 Apr;117(8):1281–83. doi:10.1242/jcs.00963
104. Villarino AV, Kanno Y, O'Shea JJ. Mechanisms and consequences of JAK–STAT signaling in the immune system. Nat Immunol. 2017 Apr;18(4):374–84. doi:10.1038/ni.3691
105. Schroder K, Tschopp J. The inflammasomes. Cell. 2010 Mar;140(6):821–32. doi: 10.1016/j.cell.2010.01.040
106. Zandi P, Schnug E. Reactive oxygen species, antioxidant responses and implications from a microbial modulation perspective. Biology (Basel). 2022 Feb;11(2):155. doi:10.3390/biology11020155
107. Ci??y?ska M, Olejniczak-Staruch I, Sobolewska-Sztychny D, Narbutt J, Skibi?ska M, Lesiak A. The role of NLRP1, NLRP3, and AIM2 inflammasomes in psoriasis. Int J Mol Sci. 2021 May 31;22(11):5898. doi:10.3390/ijms22115898
108. Kelley N, Jeltema D, Duan Y, He Y. The NLRP3 inflammasome: an overview of mechanisms of activation and regulation. Int J Mol Sci. 2019 Jul;20(13):3328. doi:10.3390/ijms20133328
109. Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008 Jul; 454:428-435. doi:10.1038/nature07201
110. Serhan CN. Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annu Rev Immunol. 2007 Apr 23;25(1):101–137. doi: 10.1146/annurev.immunol.25.022106.141647
111. Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol. 2014 Oct;6: a016295. doi:10.1101/cshperspect. a016295
112. Vane JR, Botting RM. Mechanism of action of nonsteroidal anti-inflammatory drugs. Am J Med. 1998 Mar; 104:2S-8S. doi:10.1016/S0002-9343(97)00203-9
113. Oyesola OO, Tait Wojno ED. Prostaglandin regulation of type 2 inflammation: From basic biology to therapeutic interventions. Eur J Immunol. 2021 Oct;51(10):2399–2416. doi:10.1002/eji.202048999
114. Grosser T, Smyth E, FitzGerald GA. Anti-inflammatory drugs and the cardiovascular system. J Clin Invest. 2006 Jan; 116:4–15. doi:10.1172/JCI27962
115.  Warner TD, Mitchell JA. Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic. FASEB J. 2004 Jun; 18:790–804. doi: 10.1096/fj.03-0645rev
116. Dinarello CA. Anti-inflammatory agents: present and future. Cell. 2010 Mar 19;140(6):935-50. doi: 10.1016/j.cell.2010.02.043
117. Rhen T, Cidlowski JA. Anti-inflammatory action of glucocorticoids. N Engl J Med. 2005 Oct; 353:1711–23. doi:10.1056/NEJMra050541
118. Barnes PJ. Mechanisms of action of glucocorticoids in asthma. Am J Respir Crit Care Med. 1996 Aug;154: S21–26. doi:10.1164/ajrccm.154.2_Pt_2. S21
119. Liu D, Ahmet A, Ward L, Krishnamoorthy P, Mandelcorn ED, Leigh R, Brown JP, Cohen A, Kim H. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol. 2013 Aug 15;9(1):30. doi:10.1186/1710-1492-9-30
120. Feldmann M, Maini RN. TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nat Med. 2003 Oct; 9:1245–50. doi:10.1038/nm939
121. Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action. Pharmacol Ther. 2008 Feb; 117:244–79. doi: 10.1016/j.pharmthera.2007.10.001
122. Tanaka T, Narazaki M, Kishimoto T. Therapeutic targeting of the IL-6 receptor. Annu Rev Pharmacol Toxicol. 2012 Feb; 52:199–219. doi:10.1146/annurev-pharmtox-010611-134715
123. Blauvelt A. IL-17 inhibition in psoriasis. N Engl J Med. 2016 Sep; 375:1301–02. doi:10.1056/NEJMe1609773
124. O'Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med. 2015 Jan; 66:311–28. doi:10.1146/annurev-med-051113-024537
125. Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O'Shea JJ. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov. 2017 Dec; 16:843–62. doi:10.1038/nrd.2017.201
126. Taylor PC, Keystone EC, van der Heijde D, Weinblatt ME, Del Carmen Morales L, Reyes Gonzaga J, et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med. 2017 Feb; 376:652–62. doi:10.1056/NEJMoa1608345
127. Peters-Golden M, Henderson WR. Leukotrienes. N Engl J Med. 2007 Nov; 357:1841–54. doi:10.1056/NEJMra071371
128. Drazen JM, Israel E, O’Byrne PM. Treatment of asthma with drugs modifying the leukotriene pathway. N Engl J Med. 1999 Jan; 340:197–206. doi:10.1056/NEJM199901213400307
129. Pan MH, Lai CS, Ho CT. Anti-inflammatory activity of natural dietary flavonoids. Food Funct. 2010 Jan; 1:15–31. doi:10.1039/c0fo00103a
130. Calixto JB, Campos MM, Otuki MF, Santos AR. Anti-inflammatory compounds of plant origin. Part II. Planta Med. 2004 Feb; 70:93–103. doi:10.1055/s-2004-815483
131. Serafini M, Peluso I, Raguzzini A. Flavonoids as anti-inflammatory agents. Proc Nutr Soc. 2010 Aug; 69:273-278. doi:10.1017/S002966511000162X
132. Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008 Jul ;454(7203):428–35. doi:10.1038/nature07201
133. Nathan C, Ding A. Nonresolving inflammation. Cell. 2010 Mar;140(6):871–82. doi: 10.1016/j.cell.2010.02.029
134. Barnes PJ. Anti-inflammatory actions of glucocorticoids. Clin Sci. 1998 Jun;94(6):557–72. doi:10.1042/cs0940557
135. Smolen JS, Aletaha D. Rheumatoid arthritis therapy reappraisal. Lancet. 2015 Nov;386(9990):1823–34. doi:10.1016/S0140-6736(15)60726-6
136. Calder PC. Polyunsaturated fatty acids and inflammatory processes. Biochem Soc Trans. 2005 Apr;33(2):423–27. doi:10.1042/BST0330423
137. Straub RH, Cutolo M. Glucocorticoids and chronic inflammation. Rheumatology. 2016 Dec;55(suppl 2): ii6–14. doi:10.1093/rheumatology/kew348
138. Fardet L, et al. Corticosteroid-induced adverse events. PLoS Med. 2007 Sep;4(9): e272. doi: 10.1371/journal.pmed.0040272
139. Listing J, et al. Infections in patients treated with biologics. Arthritis Rheum. 2005 Nov;52(11):3403–12. doi:10.1002/art.21386
140. Bongartz T, et al. Anti-TNF therapy and infection risk. JAMA. 2006 May;295(19):2275–85. doi:10.1001/jama.295.19.2275
141. Dinarello CA. Proinflammatory cytokines. Chest. 2000 Feb;118(2):503–08. doi:10.1378/chest.118.2.503
142. Flynn JL, Chan J. TNF and tuberculosis. Immunity. 2001 May;14(5):463–66. doi:10.1016/S1074-7613(01)00134-4
143. Winthrop KL. Risk of infection with biologic therapies. Nat Rev Rheumatol. 2017 Apr;13(4):234–43. doi:10.1038/nrrheum.2017.21
144. Blackstone EA, Fuhr JP. Economics of biosimilars. Am Health Drug Benefits. 2013 Oct;6(8):469–78.
145. Walsh G. Biopharmaceutical benchmarks. Nat Biotechnol. 2018 Dec;36(12):1136–45. doi:10.1038/nbt.4305
146. Cohen SB, et al. Cost considerations in biologic therapy. Rheumatology. 2007 Jun;46(6):849–52. doi:10.1093/rheumatology/kel410
147. Michaud K, et al. Costs of rheumatoid arthritis. Arthritis Rheum. 2003 Oct;48(10):2750–62. doi:10.1002/art.11299
148. McCamish M, Woollett G. Biosimilars development. Clin Pharmacol Ther. 2012 Mar;91(3):405–17. doi:10.1038/clpt.2011.343
149. Lanas A, Chan FKL. NSAID-induced GI toxicity. Lancet. 2017 Aug;390(10090):613–24. doi:10.1016/S0140-6736(17)31226-9
150. Grosser T, et al. NSAID cardiovascular effects. J Clin Invest. 2017 Feb;127(2):459–70. doi:10.1172/JCI90625
151. Schäcke H, et al. Mechanisms of glucocorticoid side effects. Pharmacol Ther. 2002 Apr;96(1):23–43. doi:10.1016/S0163-7258(02)00297-8
152. Hansel TT, et al. Safety of biologics. Nat Rev Drug Discov. 2010 Apr;9(4):325–38. doi:10.1038/nrd3003
153. Singh JA, et al. Adverse effects of biologics. Cochrane Database Syst Rev. 2011 Feb; CD008794. doi: 10.1002/14651858.CD008794.pub2
154. Firestein GS, McInnes IB. Immunopathogenesis of rheumatoid arthritis. Immunity. 2017 Feb;46(2):183–96. doi: 10.1016/j.immuni.2017.02.006
155. Klareskog L, et al. Gene-environment interactions in rheumatoid arthritis. Lancet. Feb 2009;373(9660):659–672. doi:10.1016/S0140-6736(09)60088-9
156. Lawrence T. Regulation of inflammatory responses. Nat Rev Immunol. Jun 2009;9(6):428–439. doi:10.1038/nri2565
157. Sze E, Bhalla A, Nair P. Mechanisms and therapeutic strategies for non?T2 asthma. Allergy. 2020 Feb;75(2):311-25. doi:10.1111/all.14017
158. Strand V, et al. Immunogenicity of biologics. Nat Rev Rheumatol. Mar 2017;13(3):164–172. doi:10.1038/nrrheum.2016.205
159. Garcês S, et al. Anti-drug antibodies. Front Immunol. Oct 2013; 4:238. doi:10.3389/fimmu.2013.00238
160. O’Neill LAJ, et al. Inflammation and therapeutic targeting. Nat Rev Drug Discov. Apr 2016;15(4):273–289. doi:10.1038/nrd.2016.34
161. Fullerton JN, Gilroy DW. Resolution of inflammation. Nat Rev Drug Discov. Aug 2016;15(8):551–567. doi:10.1038/nrd.2016.39
162. Lamkanfi M, Dixit VM. Inflammasomes and their roles. Cell. May 2014;157(5):1013–1022. doi: 10.1016/j.cell.2014.04.007
163. Guo H, et al. Inflammasomes in disease. Nat Med. Jul 2015;21(7):677–687. doi:10.1038/nm.3893
164. Coll RC, et al. MCC950 inhibits NLRP3 inflammasome. Nat Med. Mar 2015;21(3):248–255. doi:10.1038/nm.3806
165. Naldini L. Gene therapy returns to centre stage. Nature. Oct 2015;526(7573):351–360. doi:10.1038/nature15818
166. Kanasty R, et al. Delivery materials for siRNA therapeutics. Nat Mater. Nov 2013;12(11):967–977. doi:10.1038/nmat3765
167. Bobbin ML, Rossi JJ. RNA interference therapeutics. Annu Rev Pharmacol Toxicol. Jan 2016; 56:103–122. doi:10.1146/annurev-pharmtox-010715-103633
168. Whitehead KA, et al. Challenges in siRNA delivery. Nat Rev Drug Discov. Feb 2009;8(2):129–138. doi:10.1038/nrd2746
169. Peer D, et al. Nanocarriers as an emerging platform. Nat Nanotechnol. Dec 2007;2(12):751–760. doi:10.1038/nnano.2007.387
170. Petros RA, DeSimone JM. Strategies in nanoparticle delivery. Nat Rev Drug Discov. Aug 2010;9(8):615–627. doi:10.1038/nrd2591
171. Allen TM, Cullis PR. Liposomal drug delivery systems. Science. Mar 2004;303(5665):1818–1822. doi:10.1126/science.1095833
172. Torchilin VP. Multifunctional nanoparticles. Nat Rev Drug Discov. Nov 2014;13(11):813–827. doi:10.1038/nrd4333
173. . Shi J, et al. Nanotechnology in drug delivery. Nat Rev Cancer. Jan 2017;17(1):20–37. doi:10.1038/nrc.2016.108
174. Pan MH, Lai CS. Anti-inflammatory natural compounds. Mol Nutr Food Res. Jan 2012;56(1):81–94. doi:10.1002/mnfr.201100329
175. Aggarwal BB, Harikumar KB. Curcumin: molecular mechanisms of action. Int J Biochem Cell Biol. Jan 2009;41(1):40–59. doi: 10.1016/j.biocel.2008.06.010
176. Baur JA, Sinclair DA. Therapeutic potential of resveratrol. Nat Rev Drug Discov. Jun 2006;5(6):493–506. doi:10.1038/nrd2060
177. Li Y, et al. Quercetin: anti-inflammatory effects. Nutrients. Mar 2016;8(3):167. doi:10.3390/nu8030167
178. Anand P, et al. Bioavailability of curcumin: problems and promises. Mol Pharm. Dec 2007;4(6):807–818. doi:10.1021/mp700113r