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Immunological Medicine

Volume 43, 2020 - Issue 2
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Review Article

New insights into IFN-γ in rheumatoid arthritis: role in the era of JAK inhibitors

Masaru Kato Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, JapanCorrespondencektmasaru@med.hokudai.ac.jp
Pages 72-78
Received 15 Feb 2020
Accepted 30 Mar 2020
Published online: 25 Apr 2020

Review Article

New insights into IFN-γ in rheumatoid arthritis: role in the era of JAK inhibitors

Abstract

Abstract

The treatment of rheumatoid arthritis (RA) is now entering a new era, the era of Janus kinase (JAK) inhibitors. JAK inhibitors target multiple cytokines including IL-6 and exhibit a beneficial treatment effect in patients with RA and inadequate response to conventional synthetic or biologic disease-modifying anti-rheumatic drugs. Since the treatment effect of JAK inhibitors is promising even for patients refractory to anti-IL-6 therapy, it needs to be considered how multiple cytokines play roles in the pathogenesis of RA. It is also worth noting that an increased risk of herpes zoster is specifically related to the use of JAK inhibitors. Among cytokines targeted by JAK inhibitors, the current review focuses on IFN-γ, particularly on its role in synovial biology, autoimmunity, bone metabolism, pain, and varicella zoster virus infection. Recent studies provided new insights into IFN-γ in the pathogenesis of RA, which may account for the efficacy of JAK inhibitors.

1. Introduction

The cytokine interferon-gamma (IFN-γ), which is the sole member of type II interferons, plays an important role in the innate and adaptive immune responses. Since it activates monocytes/macrophages and induces the expression of major histocompatibility complex (MHC) class II on the cells, several basic and clinical studies have hypothesized its contribution to the development and progression of rheumatoid arthritis (RA), an autoimmune disorder accompanied by the activation of monocytes/macrophages [1]. Conversely, based on the mutually antagonistic effect of IFN-γ and tumor necrosis factor (TNF)-α, recombinant IFN-γ was once attempted to treat RA [2]. Anti-IFN-γ and anti-TNF-α antibodies showed similar efficacy in patients with active RA [3], whereas a more recent phase 2 clinical trial investigating the use of fontolizumab, a humanized anti-IFN-γ monoclonal antibody, for RA was terminated in 2006 because it did not meet the primary endpoint ACR50 at week 14 [4]. Janus kinase (JAK) inhibitors target multiple cytokines including IFN-γ and interleukin (IL)-6 and exhibit a beneficial treatment effect in patients with RA and inadequate response to conventional synthetic or biologic disease-modifying anti-rheumatic drugs (DMARDs) [5–7]. Even for patients refractory to anti-IL-6 therapy, the treatment effect of JAK inhibitors is promising [8,9], putatively indicating roles of multiple cytokines in the pathogenesis of RA. Among cytokines targeted by JAK inhibitors, the current review focuses on IFN-γ, particularly on its role in synovial biology, autoimmunity, and bone metabolism.

2. Signaling pathway of IFN-γ

IFN-γ interacts with its receptor to trigger cellular responses. The IFN-γ receptor consists of two transmembrane chains, IFN-γR1 and IFN-γR2, both of which are required for IFN-γ signaling. Deficiency in IFN-γR1 and that in IFN-γR2 are both associated with mendelian susceptibility to mycobacterial disease [10]. After ligand-receptor binding, two members of JAK, JAK1 and JAK2, interact with the intracellular domain of IFN-γ receptor and are activated by phosphorylation. The requisite recruitment site for signal transducer and activator of transcription (STAT) 1 is then formed, leading to STAT1 phosphorylation and homodimer formation. STAT1 homodimers translocate to the nucleus and ultimately bind to the DNA to modulate gene transcription (Figure 1). Besides the above mentioned canonical JAK-STAT pathway, IFN-γ signaling may involve noncanonical routes, such as endocytosis and ATP-dependent nuclear translocation of IFN-γ, IFN-γR1, JAK1, and JAK2 [11], which, as many other cytokines also use STAT1 as a transcription factor, might account for specific gene activation. In addition, several other kinases, including PI3K [12], CamKII [13], NF-κB [14], and ATM [15], either cooperate with or operate in parallel to JAK-STAT pathway for a full IFN-γ response. IFN-γ is produced by multiple cell types, including T cells (particularly Th1 subtype), B cells, monocytes/macrophages, and NK cells [16]. In RA synovium, CD8+ T cells are revealed to be the dominant source of IFN-γ, which is in contrast to the production of TNF-α by multiple T cell subsets, B cells, and monocytes and that of IL-6 by fibroblasts and B cells [17]. IFN-γ signaling can modulate a huge number of genes. There are more than 9,000 genes regulated by IFN-γ with two or more-fold changes [18]. Although many of genes regulated by IFN-γ are targets shared with type I IFN [19], specific functions of IFN-γ are suggested by the incomplete response to IFN-α therapy in some patients with IFN-γ receptor deficiency [20]. In physiological immunity, IFN-γ plays roles in production of reactive oxygen species, cytokine production, antigen presentation including MHC class II induction, metabolic pathways, cellular differentiation including macrophage activation (polarization towards M1 subtype), and cell growth and survival [16]. The fact that MHC class II variation (shared epitope) is the strongest genetic risk factor for RA raises a simple hypothesis that the MHC class II-inducing cytokine IFN-γ contributes to the development of RA. Polymorphisms in the IFN-γR2 gene are also associated with RA susceptibility [21].

Figure 1. Canonical signaling pathway of IFN-γ. IFN-γ interacts with its receptor to trigger cellular responses. The IFN-γ receptor consists of two transmembrane chains, IFN-γR1 and IFN-γR2. After ligand-receptor binding, two members of JAK, JAK1 and JAK2, interact with the intracellular domain of IFN-γ receptor and are activated by phosphorylation. The requisite recruitment site for signal transducer and activator of transcription (STAT) 1 is then formed, leading to STAT1 phosphorylation and homodimer formation. STAT1 homodimers translocate to the nucleus and ultimately bind to the DNA to modulate gene transcription. P, phosphate.

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3. IFN-γ in synovial biology

Since synovial inflammation is a hallmark of RA, the understanding of synovial biology and pathophysiology may be the best way to approach the pathogenesis of RA which has not yet been fully elucidated. A recent single-cell transcriptomics and mass cytometry study of synovial tissues by Zhang et al. [17] has moved our understanding of RA pathogenesis forward to a significant degree. By single-cell RNA sequencing on composite cell populations in the synovium, they identified four, four, three, three, and four distinct subpopulations of fibroblasts, monocytes, CD4+ T cells, CD8+ T cells, and B cells/plasmablasts, respectively. In the synovium of RA, compared to that of osteoarthritis (OA), a fibroblast subset highly expressing MHC class II, IL-6, and IFN-γ-inducible protein 30 was overabundant with more than 15-fold difference. A monocyte subset abundant in RA synovium expressed genes induced by type I IFN and IFN-γ. Furthermore, a CD8+ T cell subset producing IFN-γ was enriched in RA synovium. These results strongly support a putative role of IFN-γ and a possible contribution of CD8+ T cells, the latter of which may not be targeted by conventional antirheumatic therapies including abatacept [22], in the local inflammatory state in RA synovium. Conversely, IFN-γ-producing CD8+ T cells also produce an anti-inflammatory cytokine IL-10, which is suggested to act as a negative feedback system [23]. The pathogenic role of IFN-γ as an upstream regulator in RA synovium has also been shown by meta-analysis across datasets of gene expression microarray [24]. Another recent study by Bergström et al. [25] has demonstrated a novel role for the autoimmune regulator (AIRE), a master regulator of T cell tolerance in the thymus, in IFN-γ signature in synovial fibroblasts. By RNA sequencing, they identified 3,492 differentially expressed genes, including AIRE, in synovial fibroblasts following treatment with TNF-α and IL-1β. Since polymorphisms in the AIRE gene are associated with RA susceptibility [21], they focused on the role of AIRE for further analysis. AIRE expression was not detected in unstimulated synovial fibroblasts but strikingly induced following TNF-α or IL-1β treatment. The induction of AIRE was more pronounced in synovial fibroblasts from RA patients than those from OA patients. siRNA-mediated AIRE gene silencing revealed that 96% of genes regulated by AIRE in synovial fibroblasts were IFN-responsive genes with a great predominance of IFN-γ-responsive genes (95.5%). These data suggest a mechanism to boost IFN-γ signature in activated or epigenetically modified synovial fibroblasts.

4. IFN-γ in autoimmunity

Autoimmunity against citrullinated proteins is another hallmark of RA. Anti-citrullinated protein/peptide antibodies (ACPA) recognize and bind to citrullinated epitopes present on numerous proteins, such as vimentin, α-enolase, and fibrinogen [26]. Among ACPA, anti-citrullinated vimentin antibodies are particularly associated with joint destruction [27], indicating citrullinated vimentin as a major autoantigen in RA. However, given that vimentin is expressed exclusively in mesenchymal cells including fibroblasts, it needs to be considered how such non-immune cells (non-professional antigen presenting cells) play a role in RA autoimmunity. Whereas professional antigen presenting cells, such as dendritic cells, monocytes/macrophages, and B cells, constantly express MHC class II, non-immune cells including synovial fibroblasts need IFN-γ stimulation to express MHC class II [28,29]. Although synovial fibroblasts lack costimulatory molecules CD80 and CD86, CD276 (B7-H3) on those cells has been shown to act as a CD28 ligand [30]. Our recent study has provided novel mechanistic insights in the presentation of citrullinated vimentin [31]. Upon stimulation with IFN-γ, synovial fibroblasts expressed MHC class II, CD274 (PD-L1), and CD273 (PDCD1LG2), while CD276 (B7-H3) was expressed regardless of the presence of IFN-γ. Following induction of autophagy by starvation or proteasome inhibition [32], citrullinated vimentin was increased in synovial fibroblasts. By combining IFN-γ stimulation and autophagy induction, the interaction between MHC class II and citrullinated vimentin was increased. The increase of MHC class II–citrullinated vimentin interaction was more pronounced in synovial fibroblasts from RA patients than those from OA patients, consistent with the previous studies showing high autophagic activity in RA synovial fibroblasts [33,34]. These findings may partly account for the autoimmunity against mesenchymal cell-specific antigens and are relevant to IFN-γ-abundant conditions in RA synovium which have already been discussed in the previous section. A number of studies have so far indicated IFN-γ-secreting CD4+ T cells (Th1 subtype), whose differentiation is also promoted by IFN-γ, as effector cells in RA [35]. A skewing towards T cells with a Th1 cytokine profile including IFN-γ was observed in synovial fluids from RA patients [36]. A recent meta-analysis of gene expression microarray datasets also identified Th1 activation as one of the most significant pathways in RA synovium [24]. Moreover, around 40% of citrulline-specific T cells were found to be Th1 marker CXCR3-positive in the peripheral blood of RA patients [37]. All in all, IFN-γ may activate both antigen presenting cells and CD4+ T cells and thereby contributes to the autoimmunity in RA.

5. IFN-γ in bone metabolism

Periarticular and systemic bone loss is the most important clinical feature of RA, adversely affecting patients’ activities of daily living and quality of life. IFN-γ can increase alkaline phosphatase activity and a transcription factor Runx2 expression and promote osteoblast differentiation [38,39], although underlying signaling pathways have not yet become clear. In osteoclast differentiation, dual role of IFN-γ has been reported. IFN-γ directly suppresses osteoclastogenesis by counterbalancing the action of receptor activator of NF-κB (RANK) ligand (RANKL) in osteoclast precursor cells. IFN-γ signaling results in the activation of ubiquitin-proteasome system and subsequent degradation of the RANK adapter protein TRAF6 [40]. IFN-γ also inhibits the expression of RANK and that of NFATc1, a master transcription factor for osteoclastogenesis [41,42]. However, the degradation of TRAF6 by IFN-γ occurs only in the copresence of RANK signaling [40]. Furthermore, an abundance of RANKL might cancel the counterbalance by IFN-γ [42]. On the other hand, IFN-γ can activate CD4+ T cells to produce RANKL and TNF-α through enhanced MHC class II expression on antigen presenting cells and CXCL10 (IFN-γ-inducible protein 10) secretion by monocytes/macrophages [43,44]. TNF-α, in combination with IL-6, can promote osteoclast differentiation in a RANKL-independent manner [45]. These indirect pro-osteoclastogenic effects of IFN-γ might overcome its direct anti-osteoclastogenic activity under conditions of estrogen deficiency, infection, and inflammation [43,46]. Given the finding by a recent study that RANKL expressed on synovial fibroblast membrane plays an imperative role in bone erosions during joint inflammation [47], it is worth investigating how multiple cytokines act on those cells to express RANKL [48]. Our recent study has shown that IFN-γ increases RANKL expression on synovial fibroblasts without affecting the levels of osteoprotegerin, an endogenous decoy receptor for RANKL [49]. From a more clinical point of view, recombinant IFN-γ-1b is currently used to slow the progression of severe subtype of osteopetrosis, a genetic disorder associated with osteoclast dysfunction [50]. However, a recent clinical trial has failed to show the effectiveness of recombinant IFN-γ-1b for patients with a milder form of osteopetrosis (autosomal dominant type) [51]. Further studies are warranted to clarify which role of IFN-γ, direct anti-osteoclastogenic or indirect pro-osteoclastogenic role, is dominant in the joints of RA patients and whether IFN-γ plays different roles in different patients or in different stages.

6. IFN-γ in pain

In 2017, the superiority of JAK inhibitor (baricitinib, a JAK1/JAK2 inhibitor) over biologic DMARD (adalimumab, an anti-TNF-α antibody) was for the first time demonstrated in terms of clinical improvements in patients with RA [6]. Interestingly, the improvement of patients reported outcomes, such as pain, fatigue, and quality of life, rather than that of tender or swollen joints assessed by the physician were correlated with the use of baricitinib [6,52]. Based on the findings of some basic studies, the role of IFN-γ in pain processing can be speculated. Upon peripheral nerve injury, IFN-γ is upregulated in the dorsal horn [53]. IFN-γ directly activates spinal microglia [54] and subsequently potentiates NMDA receptor signaling in the neuron, which is critical in chronic pain hypersensitivity, via microglia-neuron interactions [55].

7. IFN-γ in varicella zoster virus (VZV) infection

The current review finally highlights the role of IFN-γ in the adverse events seen with JAK inhibition. An increased risk of herpes zoster is most specifically related to the use of JAK inhibitors among patients with RA or other immune-mediated diseases [56,57]. It is also worth noting that the risk of infection with other viruses, such as cytomegalovirus and Epstein-Barr virus, has not been increased with JAK inhibition [58], suggesting a special connection between JAK-STAT pathway and immunity to VZV. Given the findings that patients with multiple myeloma, which is associated with humoral immunity defects, present with increased herpes zoster incidence only after treatment with the proteasome inhibitor bortezomib [59], cell-mediated immunity may play a greater role than humoral immunity in the host defense against VZV. Both type I IFN and IFN-γ have been shown to act on the cells to restrict VZV replication and spread [60,61]. IFN-γ-IRF1 axis was more potent than IFN-α-IRF9 axis in blocking VZV infection of primary human fibroblasts [60]. Conversely, in some cell lines (e.g., MeWo melanoma cells), IFN-β, but not IFN-γ, exerted an anti-VZV activity [61]. The defensive role of type I IFN against VZV infection is also supported by a clinical trial revealing an increased incidence of herpes zoster with the use of anifrolumab, a human anti-type I IFN receptor monoclonal antibody, for patients with systemic lupus erythematosus [62]. The safety profiles of a JAK2 selective inhibitor fedratinib suggest a dominant role of JAK1 over JAK2 in the immune response against VZV [63,64].

8. Conclusion

As discussed above, a number of clinical and basic studies have demonstrated roles of IFN-γ in the pathogenesis of RA, including synovial inflammation, autoimmunity against citrullinated proteins, and periarticular and systemic bone loss (Figure 2), which may at least partially account for the efficacy of JAK inhibitors in patients with inadequate response to biologic DMARDs including anti-IL-6 antibodies. The higher risk of herpes zoster with the use of JAK inhibitors than that of biologic DMARDs may also be in part due to targeting IFN-γ signaling. Conversely, given the clinical trial failure on fontolizumab, targeting only IFN-γ seems unsuccessful to treat RA, putatively indicating roles of multiple cytokines. Further studies are desired to identify patients who have multiple cytokines against them and would therefore benefit from JAK inhibition rather than mono-targeted therapy.

Figure 2. The role of IFN-γ in the joint/synovium of patients with rheumatoid arthritis. CD8+ T cells are the dominant source of IFN-γ, which is in contrast to the production of TNF-α by multiple T cell subsets, B cells, and monocytes and that of IL-6 by synovial fibroblasts and B cells. IFN-γ activates CD4+ T cells, synovial fibroblasts, and monocytes/macrophages. Major histocompatibility complex class II (MHC II), autophagy, and citrullination in synovial fibroblasts may be involved in the production of anti-citrullinated protein/peptide antibodies (ACPA). RANKL expressed on synovial fibroblasts contributes strongly to osteoclastogenesis in the joints. Conversely, IFN-γ directly suppresses osteoclastogenesis by counterbalancing the action RANKL.

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Disclosure statement

No potential conflict of interest was reported by the author(s).

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