Semaphorin 5A promotes Th17 differentiation via PI3K-Akt-mTOR in systemic lupus erythematosus

Previously, we reported that serum Semaphorin 5 A (Sema5A) levels were increased in systemic lupus erythematosus (SLE) patients compared with healthy controls (HC), and elevated Sema5A correlated with disease activity and lupus nephritis in SLE patients. In this study, we aimed to further understand the role of Sema5A in promoting Th17 cells differentiation in SLE. Sema5A, interferon gamma (IFN-γ), interleukin 4 (IL-4), interleukin 17 A (IL-17 A) and interleukin 10 (IL-10) were measured by Enzyme Linked Immunosorbent Assay (ELISA). RNA and protein were isolated from peripheral blood mononuclear cells (PBMCs) in SLE patients and HC. Expression of PlexinA1 and PlexinB3 were measured by quantitative RT-PCR (qRT-PCR) and Western Blot. Th cell subsets were detected by flow cytometry. Treatment with recombinant human Sema5A (rhSema5A) and small interfering RNA (siRNA) were employed to examine the in vitro effect of Sema5A in CD4+T cell differentiation in SLE patients. IL-17 A elevated in SLE patients and positively correlated with Sema5A. PlexinA1 was upregulated and mainly expressed in CD4+ T cells of SLE; Sema5A treatment induced the differentiation of Th17 cells, while did not affect the Th1 and Th2 skewing. These effects were associated with an upregulation of the transcription factor RORγt by Th17 cells, but not T-bet or GATA3 in Th1 and Th2 cells, respectively. Knock down PlexinA1 regulates IL-17 A production by CD4+T cells. Functional assays showed that Sema5A-PlexinA1 axis promoted Th17 cells differentiation via PI3K/Akt/mTOR signaling. These findings demonstrated that Sema5A-PlexinA1 axis acts as a key mediator on Th17 differentiation, suggesting that Sema5A might be a novel therapeutic target in SLE.