The potential of PTPN22 as a therapeutic target for rheumatoid arthritis

ABSTRACT

Introduction: PTPN22 encodes a lymphoid-specific tyrosine phosphatase (LYP) that is a master regulator of the immune response. This gene is a major susceptibility factor for a wide range of autoimmune conditions, including rheumatoid arthritis (RA) for which it represents the strongest non-HLA contributor to disease risk. A missense PTPN22 allele (R620W) affecting the protein-protein interaction of LYP with other relevant players was described as the functional variant of the association. This review will focus on the role of PTPN22 in the pathogenic mechanisms underlying RA predisposition and discuss the possibility of developing LYP-based treatment strategies with a potential application in clinical practice.

Areas covered: This review covers the literature showing how PTPN22 is implicated in signalling pathways involved in the autoimmune and autoinflammatory processes underlying RA. Insights obtained from studies aimed at developing novel selective LYP suppressors for treating RA are summarized.

Expert opinion: Targeting key risk factors during the early steps of the disease may represent a good strategy to accomplish complete disease remission. As cumulating evidences suggest that PTPN22 R620W is a gain-of-function variant, a growing interest in developing LYP inhibitors has arisen. The potential efficacy and possible application of such compounds are discussed.     

T cell immunoglobulin-3 as a new therapeutic target for rheumatoid arthritis

T cell immunoglobulin-3 (Tim-3) is a surface molecule expressed on various cell types of the immune system which plays a central role in immune regulation. Recently, identi?cation of galectin-9 (Gal-9) as a ligand for Tim-3 has established the Tim-3–Gal-9 pathway as an important regulator of Th1 immunity and induction of tolerance. The interaction of Tim-3 with Gal-9 induces cell death; the in vivo blockade of this interaction results in exacerbated autoimmunity and abrogation of tolerance in experimental models, thus establishing Tim-3 as a negative regulatory molecule. A number of previous studies have demonstrated that Tim-3 in?uences chronic autoimmune diseases, such as multiple sclerosis and systemic lupus erythematosus. In addition, an association between Tim-3 polymorphisms and susceptibility to several autoimmune diseases has been identi?ed in various autoimmune diseases, including rheumatoid arthritis (RA). Recent work has focused on the role of Tim-3 in RA, and the results indicate that Tim-3 may represent a novel target for the treatment of RA. In this article we will discuss the Tim-3 pathway and the therapeutic potential of modulating the Tim-3 pathway in RA.     

Prostaglandin E2 synthase inhibition as a therapeutic target

Background: Most NSAIDs function by inhibiting biosynthesis of PGE₂ by inhibition of COX-1 and/or COX-2. Since COX-1 has a protective function in the gastro-intestinal tract (GIT), non-selective inhibition of both cycloxy genases leads to moderate to severe gastro-intestinal intolerance. Attempts to identify selective inhibitors of COX-2, led to the identification of celecoxib and rofecoxib. However, long-term use of these drugs has serious adverse effects of sudden myocardial infarction and thrombosis. Drug-mediated imbalance in the levels of prostaglandin I₂ (PGI₂) and thromboxane A₂ (TXA₂) with a bias towards TXA₂ may be the primary reason for these events. This resulted in the drugs being withdrawn from the market, leaving a need for an effective and safe anti-inflammatory drug. Methods: Recently, the focus of research has shifted to enzymes downstream of COX in the prosta glandin biosynthetic pathway such as prostaglandin E₂ synthases. Microsomal prostaglandin E₂ synthase-1 (mPGES-1) specifically isomerizes PGH₂ to PGE₂, under inflammatory conditions. In this review, we examine the biology of mPGES-1 and its role in disease. Progress in designing molecules that can selectively inhibit mPGES-1 is reviewed. Conclusion: mPGES-1 has the potential to be a target for anti-inflammatory therapy, devoid of adverse GIT and cardiac effects and warrants further investigation.     

Hydrogen sulfide as a therapeutic target for inflammation

Introduction: The view of hydrogen sulfide has changed from a toxic by-product to a crucial signaling molecule, with enormous potential as a pharmacological target for diseases ranging from heart disease to sepsis. Despite this progression of ideas, there is still a large amount that is unknown about this gaseous signaling molecule. Hydrogen sulfide has been implicated as a tissue protectant in many pathological conditions, the mechanisms of tissue protection is a point of controversy, particularly distinguishing the direct actions from the indirect downstream effects of hydrogen sulfide. This point of controversy is particularly pertinent in inflammation research.

Areas covered: Current research into the pathways in which hydrogen sulfide can act as a pro-inflammatory molecule and as an anti-inflammatory molecule.

Expert opinion: How controversies regarding hydrogen sulfide may have occurred is discussed. Addressed are the direct and indirect pathways of hydrogen sulfide on inflammation, the effects of different concentrations of hydrogen sulfide and how the effects of hydrogen sulfide on the immune system vary with different delivery mechanisms. Furthermore, there is a discussion on what key gaps exist in current knowledge and must be addressed before hydrogen sulfide can be considered a valid pharmacological target.     

Leptin signaling as a therapeutic target of obesity

Introduction: Leptin is a hormone with a key role in food intake and body weight homeostasis. Congenital leptin deficiency (CLD) is a rare disease that causes hyperphagia and early severe obesity. However, common obesity conditions are associated with hyperleptinemia and leptin resistance.

Areas covered: The main signaling pathways activated by leptin as well as the mechanisms underlying the regulatory actions of leptin on food intake and on lipid and glucose metabolism are reviewed. The potential mechanisms involving leptin resistance and the main regulatory hormonal and nutritional factors controlling leptin production/functions are also analyzed. The pathophysiology of leptin in human obesity, and especially the trials analyzing effects of leptin replacement therapy in patients with CLD or in subjects with common obesity and in post-obese weight-reduced subjects are also summarized.

Expert opinion: The use of drugs or specific bioactive food components with anti-inflammatory properties to reduce the inflammatory state associated with obesity, especially at the hypothalamus, may help to overcome leptin resistance. Research should also be focused on investigating dietary strategies, food supplements or drugs capable of avoiding or reversing the leptin fall during weight management, in order to promote sustained body weight lowering and weight loss maintenance.     

Bradykinin receptors as a therapeutic target

Biologically-active kinins, including bradykinin (BK) and Lys⁰-BK (kallidin), are short-lived peptide mediators predominantly generated by the enzymatic action of kallikreins on kininogen precursors. A diverse spectrum of physiological and pathological actions attributed to local kinin production is a consequence of the activation of G-protein-coupled receptors (GPCRs). Currently, two major subtypes of kinin receptor, designated B₁ and B₂, are recognised, although there is much evidence for pharmacological heterogeneity, particularly within the B₂ receptors. Considering these facts and the widespread distribution of kinin receptors in many human tissues, it is no surprise that the therapeutic potential of kinins and kinin receptor antagonists remains the focus of numerous investigations. Studies in animals and animal tissues, instrumental in elucidating the biological roles of kinins, are well-documented in numerous excellent reviews. Unfortunately, and despite the enormous potential illustrated by animal studies, attempts to develop kinin analogues as therapeutic agents to combat human disease have largely proven disappointing. Consequently, this review selectively focuses upon studies that are directly relevant to the targeting of human BK receptors as a therapeutic intervention. In addition to providing a succinct review of well-documented pathological conditions to which kinin receptors contribute, the authors have also included more recent data that illustrate new avenues for the therapeutic application of kinin analogues.     

The IL-6/sIL-6R complex as a novel target for therapeutic approaches

IL-6 plays a pivotal role in immune responses and certain oncologic conditions. The intense investigation of its biological activity and function led to the discovery of two different IL-6-driven signalling pathways. Binding to the membrane-bound IL-6 receptor (mIL-6R, CD126) causes the recruitment of two gp130 co-receptor molecules (CD130) and the activation of intracellular signalling cascades via gp130. Although this classical pathway is mainly limited to hepatocytes, neutrophils, monocytes/macrophages and certain other leukocyte populations, which express IL-6R on their surface, an alternative mechanism has also been described. Proteolytic cleavage of the mIL-6R protein or translation from alternatively spliced mRNA leads to the generation of a soluble form of the IL-6R (sIL-6R), which is likewise able to bind to IL-6. The resulting IL-6/sIL-6R complex is also capable of binding to gp130 and inducing intracellular signalling. Through this so-called ‘trans-signalling’ mechanism, IL-6 is able to stimulate cells that lack an endogenous mIL-6R. High levels of IL-6 and sIL-6R have been reported in several chronic inflammatory and autoimmune diseases as well as in cancer. Preclinical animal disease models have provided strong evidence that specific blockade of IL-6-regulated signalling pathways represents a promising approach for the therapy of these diseases. An optimised variant of the recently described fusion protein sgp30Fc is now heading towards its clinical evaluation.     

MyD88 as a therapeutic target for inflammatory lung diseases

Introduction: Myeloid differentiation primary response protein 88 (MyD88) is a critical adaptor protein involved in Toll-like and IL-1 receptor family signaling controlling innate immune responses and inflammation. Genetic deletion of MyD88 function results in profound suppression of inflammation and reduced resistance of the host to pathogens indicating non-redundant roles of MyD88. The TIR domain is critical for MyD88 dimerization and signaling for TLR and IL-1R family receptor.

Areas covered: Emerging evidence suggests that chemical disruption of the TIR domain attenuates cell activation and inhibits in vivo MyD88-dependent inflammation. We review the development of MyD88 dimerization disruptors as a novel therapeutic approach of respiratory diseases with a focus on COPD.

Expert opinion: There is a proof of concept that therapeutic targeting of MyD88 is feasible and first preclinical data are highly promising. This opens a great opportunity to treat exacerbations of COPD and other chronic respiratory diseases. However, extensive preclinical investigations and risk analyses are required with carefully evaluation of reduced host resistance and opportunistic infections.     

Extracellular HMGB1 as a therapeutic target in inflammatory diseases

Introduction: High-mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that promotes inflammation when released extracellularly after cellular activation, stress, damage or death. HMGB1 operates as one of the most intriguing molecules in inflammatory disorders via recently elucidated signal and molecular transport mechanisms. Treatments based on antagonists specifically targeting extracellular HMGB1 have generated encouraging results in a wide number of experimental models of infectious and sterile inflammation. Clinical studies are still to come.

Areas covered: We here summarize recent advances regarding pathways for extracellular HMGB1 release, receptor usage, and functional consequences of post-translational modifications. The review also addresses results of preclinical HMGB1-targeted therapy studies in multiple inflammatory conditions and outlines the current status of emerging clinical HMGB1-specific antagonists.

Expert opinion: Blocking excessive amounts of extracellular HMGB1, particularly the disulfide isoform, offers an attractive clinical opportunity to ameliorate systemic inflammatory diseases. Therapeutic interventions to regulate intracellular HMGB1 biology must still await a deeper understanding of intracellular HMGB1 functions. Future work is needed to create more robust assays to evaluate functional bioactivity of HMGB1 antagonists. Forthcoming clinical studies would also greatly benefit from a development of antibody-based assays to quantify HMGB1 redox isoforms, presently assessed by mass spectrometry methods.     

CCR6 as a possible therapeutic target in psoriasis

Importance of the field: Psoriasis is a common, chronic autoimmune disease of the skin. Despite a number of effective treatments, new therapies are needed with enhanced efficacy, safety and convenience. Chemokine receptors are GPCRs that control leukocyte trafficking, and like other GPCRs, are good potential drug targets. The chemokine receptor CCR6 is expressed on the T_H17 subset of CD4⁺ T cells, which produces IL-17A/F, IL-22, TNF-α and other cytokines, and which has been implicated in the pathogenesis of psoriasis. CCR6 and its ligand, CCL20/MIP-3α, are highly expressed in psoriatic skin and CCR6 is necessary for the pathology induced in a mouse model of psoriasis-like inflammation.

Areas covered in this review: This review summarizes the evidence for the importance of the IL-23/T_H17 axis, and in particular CCR6 and CCL20 in psoriasis, dating from 2000 to the present, and discusses the possibility of inhibiting CCR6 as a treatment for the disease.

What the reader will gain: The review informs the reader of the current thinking on the mechanisms of inflammation in psoriasis and the possible roles for CCR6 (and CCL20) in disease pathogenesis.

Take home message: We conclude that CCR6 should be investigated as a potential therapeutic target in psoriasis.     

Macrophage migration inhibitory factor (MIF) as a therapeutic target for rheumatoid arthritis and systemic lupus erythematosus

ABSTRACT

Introduction. Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine with upstream regulatory roles in innate and adaptive immunity and is implicated in the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Several classes of MIF inhibitors such as small molecule inhibitors and peptide inhibitors are in clinical development.

Areas covered. The role of MIF in the pathogenesis of RA and SLE is examined; the authors review the structure, physiology and signaling characteristics of MIF and the related cytokine D-DT/MIF-2. The preclinical and clinical trial data for MIF inhibitors are also reviewed; information was retrieved from PubMed and ClinicalTrials.gov using the keywords MIF, D-DT/MIF-2, CD74, CD44, CXCR2, CXCR4, Jab-1, rheumatoid arthritis, systemic lupus erythematosus, MIF inhibitor, small molecule, anti-MIF, anti-CD74, and peptide inhibitor.

Expert opinion. Studies in mice and in humans demonstrate the therapeutic potential of MIF inhibition for RA and SLE. MIF- directed approaches could be particularly efficacious in patients with high expression MIF genetic polymorphisms. In patients with RA and SLE and high expression MIF alleles, targeted MIF inhibition could be a precision medicine approach to treatment. Anti-MIF pharmacotherapies could also be steroid-sparing in patients with chronic glucocorticoid dependence or refractory autoimmune disease.     

Wnt signaling as a therapeutic target for bone diseases

Background: There is a need to develop new bone anabolic agents because current bone regeneration regimens have limitations. The Wingless-type MMTV integration site (Wnt) pathway has emerged as a regulator of bone formation and regeneration. Objective: To review the molecular basis for Wnt pathway modulation and discuss strategies that target it and improve bone mass. Methods: Data in peer-reviewed reports and meeting abstracts are discussed. Results/conclusions: Neutralizing inhibitors of Wnt signaling have emerged as promising strategies. Small-molecule inhibitors of glycogen synthase kinase 3β increase bone mass, lower adiposity and reduce fracture risk. Neutralizing antibodies to Dickkopf 1, secreted Frizzled-related protein 1 and sclerostin produce similar outcomes in animal models. These drugs are exciting breakthroughs but are not without risks. The challenges include tissue-specific targeting and consequently, long-term safety.     

TGF-beta in cancer and as a therapeutic target

Cancer develops through a series of genetic changes leading to malignant transformation. Numerous gene and pathways involved in stages of progression to frank malignancy have been elucidated. These genetic changes result in aberrations in fundamental cellular processes controlling proliferation, apoptosis, differentiation and genomic stability. Metastasis is the hallmark of malignancy. The process of metastasis is extremely complex and involves steps including dissemination of tumor cells from the primary tumor through the vascular and lymphatic system and growth selectively in distant tissues and organs. Transforming growth factor-beta which is a growth suppressive cytokine in many normal situations becomes an active and important participant in malignant disease including angiogenesis, extracellular matrix deposition, immuno-suppression and metastasis growth promotion. Transforming growth factor-beta and its receptors are targets for antibody therapeutics and small molecule kinase inhibitors.     

The expanding role of IL-7 and thymic stromal lymphopoietin as therapeutic target for rheumatoid arthritis

Introduction: The discovery of IL-7 and thymic stromal lymphopoietin (TSLP) has been a major step in the understanding of arthritis. IL-7 amplifies the inflammation induced by other cytokines, primarily TNF. In animal models of arthritis, inhibition of IL-7 limits inflammation and joint erosion. TSLP is an IL-7-like cytokine that triggers dendritic cell-mediated Th2-type inflammatory responses and is considered as a master switch for allergic inflammation. TSLP is a downstream molecule of TNF-α and as such may be involved in the pathophysiology of inflammatory arthritis.

Areas covered: This review summarizes current knowledge of the role of IL-7 and TSLP derived from both animal models and studies in patients with rheumatoid arthritis (RA). The emergence of IL-7 blockade as a future therapy in RA is highlighted, along with the potential goals and limitations of this therapeutic approach. The write-up also highlights the functional capacities of TSLP in arthritis.

Expert opinion: Evidences suggest important roles for IL-7 and TSLP in the pathogenesis of RA and can be viewed as potential therapeutic targets. Regulation of these at genetic level is a promising investigational area. Given the difficulty in reconstituting T cells in patients with RA, therapeutic approaches that minimize the elimination of T cells are likely to be more desirable.