Systemic lupus erythematosus (SLE) is a typical autoimmune disease that can affect various tissues and organs throughout the body. SLE is characterized by excessive activation of the immune system, resulting in increases in autoantibodies and immune complexes and organ dysfunction (1). At present, the pathogenesis of SLE is unclear. Sun exposure or viral infection can induce the disease in individuals with genetic susceptibilities, and women are the most vulnerable group (2). With continued development of sequencing technology, SLE was found to have a distinct interferon (IFN) gene signature (3), which is found in approximately 75% of adult patients and 90% of pediatric patients (4). Interferon is a cytokine produced in response to viral infection and has various effects, such as regulating immunity, antiviral and antitumor activities (5). According to the primary protein sequence, cognate receptor, gene locus, and cell type responsible for its production, IFNs are mainly divided into three types. Type I IFNs include IFN-α subtypes and IFN-β, -ϵ, -κ, and -ω. Type II IFNs include IFN-γ. Type III IFNs include IFN-λ (6). Many studies have shown the dominance of IFN-α in SLE (7), but some studies have also indicated that the IFN-γ gene signature may occur early in SLE (8) and may have an important role in lupus nephritis (LN) (9). Some studies found that the levels of IFN-γ and its related genes were closely related to the activation of type I IFNs in SLE patients (10, 11). More importantly, treatment against IFN-α seems to have a limited effect on SLE (12, 13), while treatment against IFN-γ could be more attractive (14). Our previous studies have emphasized the important role of IFN-γ in the initial and active stages of SLE (15). Therefore, this review will focus on IFN-γ and SLE to contribute to the understanding and treatment of SLE.

IFN-γ is a pleiotropic type II IFN that is mainly produced by effector Th1 CD4⁺ T cells, cytotoxic CD8⁺ T cells and NK cells and to a lesser extent by other cell types, such as dendritic cells (DCs), macrophages and B cells (16). IFN-γ binds to the IFN-γ receptor (IFNGR), which is expressed on most cells and activates janus kinase 1 (JAK1) and JAK2 through the canonical pathway ( Figure 1 ), leading to the phosphorylation of STAT1 homodimers and binding to the IFN-γ activation site (GAS) followed by subsequent gene transcribe (17). In addition, IFN-γ can also play a role in signal transduction through noncanonical pathways (18, 19). There is significant overlap (crosstalk) between type I and type II inducible genes, and signaling pathways can be shared between the two. Each interferon type induces the production of the other, ultimately resulting in stimulation from both sides and a mixed signature (17). Therefore, it is difficult to tell the difference between the two.

Studies have shown that the level of IFN-γ in the serum of patients with SLE is higher than that in healthy individuals (20–23), and there is abnormal accumulation of IFN-γ in the body long before the diagnosis of SLE and before the appearance of autoantibodies and IFN-α (8). Both the mRNA and protein levels of IFN-γ were significantly higher in SLE patients than in healthy donors (9, 24), and the mRNA levels of type II IFN-inducible genes (IRF1, GBP1, CXCL9, CXCL10, and SERPING1) were elevated in SLE patients. In addition, the relative expression levels of the important transcription factors TBX21 and EOMES (25), which promote IFN-γ gene expression, were also elevated in SLE patients. We previously found an IFN-γ signature when analyzing the genetic signature of active SLE onset (15). Liu et al. evaluated the relationship between the IFN-γ signaling pathway and disease activity-related indicators and found that IFN-γ titers had good correlations with disease activity (25, 26). Manman et al. found that IFNG expression and the IFN-II score were positively correlated with SLEDAI scores and anti-dsDNA antibody levels but negatively correlated with serum complement third-component levels (25). Moreover, some studies also showed that the levels of IFN-γ in the serum of patients with LN were higher than those of patients with SLE without LN (27), and IFN-γ was detected in the renal tissue of patients with LN. Single-cell transcriptome analysis of kidney-infiltrating immune cells revealed that all patients produced IFN-γ (9). Furthermore, transgenic mice overexpressing IFN-γ developed autoantibodies against dsDNA and proliferative glomerulonephritis (28). Overall, the IFN-γ signaling pathway is activated in SLE patients, and IFNG levels and IFNII scores can be used as indicators of SLE disease activity to guide clinical treatment.

SLE is a disease with genetic characteristics. DNA sequence differences and epigenetic differences such as DNA methylation and acetylation can alter gene expression and play an important role in SLE (29). Single nucleotide polymorphisms (SNPs) are the most common genetic polymorphisms. Multiple IFN-γ related SNPs have been identified as risk loci in SLE. The greatest risk of developing SLE was detected in individuals with a Met14/Val14 genotype of IFNGR1 or a Gln64/Gln64 genotype of IFNGR2 (30). IFN-γ gene polymorphisms associated with susceptibility to SLE (31). Marut’s study found an association between the IFN-γ gene polymorphism (+874A) and the manifestations of SLE arthritis (32). A SNP of STAT4 (rs7574865) (33) was found to be associated with SLE in the IFN-STAT signaling pathway. In addition, many SNPs of interferon regulated factors (IRFs) have also been found to be associated with the risk of developing SLE, including IRF3 rs2304206 (34), IRF5 rs200464 (35), IRF7 rs1131665 (36), IRF8 rs11644034 and rs2280381 (37) polymorphism. More important, epigenetic regulation is an important mechanism of transcriptional activation in SLE pathogenesis. Epigenetics refers to the genetic regulation of changes in gene expression caused by changes in DNA methylation, histone acetylation, and chromatin accessibility without changing the nucleotide sequence of DNA (38). The enhanced response of Th1 cells in SLE is accompanied by transcriptional activation of the intracellular IFGN locus (39, 40), which is mainly due to various epigenetic changes such as H3K4 tri-methylation (41), H4-Ac catalyzed by histone acetyltransferase (42), and chromatin conformational remodeling (43). On the other hand, IFN-γ can also induce extensive remodeling of the epigenome (44). For example, IFN-γ induces IRF1-STAT1 and histone acetylation to mark promoters and enhancers of TNF and IL6 loci, resulting in increased inflammatory responses in response to subsequent over-induction by TLR ligand stimulation (45). Additionally, acetylation (H3K27Ac) is associated with gene expression, while trimethylation (H3K27me3) is associated with gene silencing (46). It was found that IFN-γ stably silences a small group of genes of anti-inflammatory including MERTK, PPARG and RANK by maintaining H3K27me3 at gene promoters (47). Thus, IFN-γ treatment made these genes refractory to the induction of glucocorticoids and IL-4. All these epigenetic changes involving IFN-γ promote and solidify the inflammation development of SLE.

IFN-γ is a major proinflammatory cytokine that regulates the functions of several important immune system cells ( Figure 2 ), including B cells and T cells (48, 49), and contributes significantly to the development of SLE.

Satisfactory outcomes were observed after the application of anti-IFN-γ in a mouse lupus model ( Table 1 ). Ozmen et al. found that treating NZB/W mice with soluble murine IFN-γ receptors inhibited the onset of glomerulonephritis (123). Werwitzke et al. treated lupus-prone NZB/NZW F1 mice with recombinant soluble Fc gamma receptor II (CD32), and found that it inhibited chronic murine lupus pathologyin vivo (128). Lawson et al. performed intramuscular injection of a cDNA plasmid encoding IFN-γR/Fc into MRL-Fas(lpr) lupus mice, and found that lupus development and progression could be delayed, even if the treatment was initiated at a late stage (126). Besides, in (NZB)/(NZW)F1 mice, a favorable effect was observed in the treatment of lupus nephritis using an IFN-γ monoclonal antibody in vivo (122). Furthermore, lack of IFN-RII protects MRL/lpr mice from developing severe autoimmune-related lymphadenopathy, autoantibodies, and kidney disease (127). Deletion of the IFN-γ receptor prevents autoantibody production and glomerulonephritis in lupus-prone (NZB x NZW) F1 mice (124). Additionally, Schrott et al. found that chronic soluble IFN-γ receptor treatment attenuated behavioral abnormalities in autoimmune mice (125). Human clinical trials targeting IFN-γ have yielded some results ( Table 1 ). AMG 811 is a fully human (IgG1) anti-IFN-γ antibody. In patients with mild to moderate SLE, a single dose of AMG 811 was well tolerated and could normalize IFN-regulated gene expression, resulting in a dose-dependent decrease in serum CXCL-10 levels (14, 129). AMG 811 treatment led to changes in IFN-γ-associated biomarkers and was well tolerated, but no significant clinical benefit was observed in patients with discoid lupus erythematosus (DLE) (130). Encouragingly positive phase Ib trials have shown the efficacy of blocking the IFN-γ pathway to treat extrarenal lupus (131). Collectively, these findings suggest that IFN-γ is a central cytokine in LN, and further studies of LN should examine IFN-γ inhibition given the acceptable safety profile of its direct blockade.

Janus kinases (JAKs) are intracellular non-receptor tyrosine kinases that play key roles in the signaling pathways of many cytokines. This also provides a basis for the application of JAK inhibitors in the treatment of SLE. Both type I and type II interferon conduct signal transduction through the JAK-STAT signaling pathway (132), and there are many overlaps downstream of both. Therefore, blocking the JAK pathway has both therapeutic effects on both type I IFN and type II IFN mediated disease processes. Studies have found that JAKs inhibitors can inhibit the IFN signaling in human DCs, reduce CD80/CD86 expression and T cell stimulation ability (133), and reduce the production of various inflammatory cytokines including IFN-γ (134) in SLE mice. It can also restore the balance of naive CD4⁺ T cells and effector/memory cell populations in SLE mice (135). Besides, evidence from a lupus model suggests that tofacitinib (a JAK inhibitor) reduces levels of anti-dsDNA and proteinuria, and relieve symptom of nephritis and rash (136, 137). Moreover, in clinical studies, JAKs inhibitors were also found to significantly improve the signs and symptoms of active SLE, with a high remission rate of 67% for arthritis or rash in SLE patients (138, 139).

There are genetic features of IFN-γ in SLE, especially in the initial and active stages of the disease, suggesting that IFN-γ plays an important role in the pathogenesis of SLE. IFN-γ is an important contributor to immune regulation in the body, which may be one of the roles that cannot be ignored in the pathogenesis of SLE. Moreover, current animal studies support the feasibility of targeted IFN-γ therapy in SLE; however, no obvious effect of targeted IFN therapy has been found in human clinical trials, although some of the inflammatory indicators showed significant changes compared with those in the placebo group. Whereas, these trials are designed to focus more on drug safety than efficacy. It is worth noting that due to the important role of IFN-γ in the response to infection with some viruses, such as herpesvirus and Salmonella, during targeted IFN-γ therapy also needs to be examined in more extensive population experiments. Nevertheless, the pathogenic role of IFN-γ in SLE is of interest and treatment target IFN-γ is more promising.

WL: Organize literature and original draft writing; SZ: Search literature and writing editing; JW: Conception and writing review. All authors contributed to the article and approved the submitted version.

We gratefully thank all authors.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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