The Role of STAT Signaling Pathways in the Pathogenesis of Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder with a broad spectrum of clinical presentations and association with multiple immunological abnormalities. Recent research of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway-revealed aberrant STAT signaling in inflammatory conditions and autoimmune diseases including SLE. STAT proteins are major components in interferon (IFN)-dependent gene expression and are responsible for signal transduction of over 50 cytokines, hormones, and growth factors regulating key cellular processes such as survival, proliferation, and differentiation. This review summarizes the present evidence from experimental animal models and patients with SLE for the involvement of STAT pathways in the pathogenesis of SLE underlining the role of different members of the STAT family. Genome-wide association studies provided evidence that variations in STAT4 gene are linked to the development of SLE in humans. First integration with genome-wide epigenomics data suggests that control of CD4+ T cell differentiation in which STATs play a major role may be an important component of the genetic contribution to disease susceptibility. Increased transcript and total protein STAT1 levels were described both in SLE T and B cells suggestive of the priming mechanisms that augment STAT1 signaling responses to IFN. STAT3 has a crucial role in Th17 differentiation, T follicular helper, and B cells, and STAT3 inhibition could represent a possible future therapeutic target in SLE. STAT5B appears to act as a critical modulator of human Treg development and function. While the imbalance between phosphorylated STAT5 and STAT3 in human SLE T cells was implicated in dysregulated IL-10 expression, Treg-specific deletion of STAT3 in mouse model even enhanced Th17-mediated inflammation. Finally, we present also a comprehensive analysis of studies investigating STAT signaling responses in conventional and regulatory subsets of SLE T and B cells and possible implications of STAT inhibition for clinical therapy.

Association of interleukin 22 gene polymorphisms and serum IL-22 level with risk of systemic lupus erythematosus in a Chinese population

“…The results provide information that IL-22 may be a proinflammatory factor in pSS [17]. These signalling pathways are related to the development of SLE [21,22]. IL-22 binding to the IL-22 receptor (IL-22R) complex that induces a series of downstream signalling pathways [19].…”

Current prospects of type II interferon γ signaling and autoimmunity

“…Moreover, at the cytoplasm, an increase in un-phosphorylated STAT2 binds pStat1 to diminish its nuclear translocation during continuous IFN␥ stimulation possibly eliciting adaptation to long-term IFN␥ stimulation (71). In the nuclei, protein inhibitors of activated STAT (PIAS) associate with activated STAT dimers via their zinc-binding ring finger domain in the center of the molecule, preventing them from binding to the DNA (72). Thus, a primed innate immune system modulates the functions of IFNs and defines the host response to underlying triggers of autoimmune disorders.…”

Confirmation of five novel susceptibility loci for Systemic Lupus Erythematosus (SLE) and integrated network analysis of 82 SLE susceptibility loci

“…The lead SNPs for the five candidate loci directly and strongly disrupted 24 TFBSs. rs223881 disrupts binding of SLE risk gene STAT5A (25,26), which contributes to B-cell response to cytokines and glucocorticoid receptor NR3C1 (27) Table S2). This set of correlated, disrupted TFBSs includes those for known SLE risk genes such as ETS1 (28), NF-jB (29), STAT2 and STAT3 (48).…”