Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune disease involving injuries in multiple organs and systems. Exaggerated inflammatory responses are characterized as end-organ damage in patients with SLE. Although the explicit pathogenesis of SLE remains unclear, increasing evidence suggests that dysregulation of cytokine signals contributes to the progression of SLE through the Janus kinase/signal transducer and activator of transcription (STAT) signaling pathway. Activated STAT proteins translocate to the cell nucleus and induce transcription of target genes, which regulate downstream cytokine production and inflammatory cell infiltration. The suppressor of cytokine signaling 1 (SOCS1) is considered as a classical inhibitor of cytokine signaling. Recent studies have demonstrated that SOCS1 expression is decreased in patients with SLE and in murine lupus models, and this negatively correlates with the magnitude of inflammation. Dysregulation of SOCS1 signals participates in various pathological processes of SLE such as hematologic abnormalities and autoantibody generation. Lupus nephritis is one of the most serious complications of SLE, and it correlates with suppressed SOCS1 signals in renal tissues. Moreover, SOCS1 insufficiency affects the function of several other organs, including skin, central nervous system, liver, and lungs. Therefore, SOCS1 aberrancy contributes to the development of both systemic and local inflammation in SLE patients. In this review, we discuss recent studies regarding the roles of SOCS1 in the pathogenesis of SLE and its therapeutic implications.
Highlights
As a complex autoimmune disease, systemic lupus erythematosus (SLE) is characterized by the presence of autoantibodies against self-antigens, including double-stranded DNA, as well as the risk of autoantibody-induced end-organ damage [1]
Intraperitoneal administration of suppressor of cytokine signaling 1 (SOCS1) peptidomimetic (53DTHFRTFRSHSDYRRI68), which is a peptide that mim ics the activity of the SOCS1 kinase inhibitory region (KIR) region, in mice with diabetic nephropathy suppressed the activation of signal transducer and activator of transcription 1 (STAT1) signals, reduced serum creatinine and albuminuria levels, and ameliorated mesangial expansion, tubular injury, and renal fibrosis [77]
The SOCS1 pathway is a key regulator of inflammatory cytokines, which are pivotal in the progression of SLE
Summary
As a complex autoimmune disease, systemic lupus erythematosus (SLE) is characterized by the presence of autoantibodies against self-antigens, including double-stranded (ds) DNA, as well as the risk of autoantibody-induced end-organ damage [1]. After binding to phosphorylated JAK2, SOCS1 dephosphorylates and forms a complex, with JAK2, which leads to irreversible JAK2 degradation (Figure 1C) [18] Under these interactions, the phosphorylation of STAT1 is hindered and immune responses, such as IFN-γ signaling, inflammatory factor production, T cell development and activation, etc., are suppressed [19, 20]. The SOCS1 transgenic mice were constructed by applying the lck proximal promoter to drive transgenic expression only in the T cell lineage [38] In these mice, tyrosine phosphorylation of STAT1 that is responsive to cytokines, such as IFN-γ, IL-6, and IL-7, was significantly suppressed; and the number of thymocytes decreased due to the blockade of development in the triple-negative stage, which led to an increase in the percentage of CD4+ T cells [38].
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