SOCS1 improves abnormal IgA galactosylation in IgA nephropathy by regulating the TLR9/MyD88 pathway

Abnormal galactosylation of IgA is a core factor in the development of IgA nephropathy (IgAN). Suppressor of cytokine signaling 1 (SOCS1) expression negatively correlates with IgA1 secretion in IgAN patients and that TLR9/MyD88 promotes aberrantly glycosylated IgA formation. Therefore, the present study exposed whether SOCS1 is involved in aberrant galactosylation of IgA in IgAN by regulating the TLR9/MyD88 signaling pathway through in vivo and in vitro experiments. Differential expression of SOSC1 in IgAN patients and non-IgAN patients was analyzed using bioinformatics analysis and immunofluorescence. The IgAN mouse model and the IgA1-secreting DAKIKI cell model were used to validate the effect of SOCS1 on aberrant IgA galactosylation in IgAN. In addition, qRT-PCR, western blot, and immunohistochemistry experiments were performed to reveal the regulation of the TLR9/MyD88 pathway by SOCS1 in IgAN. The expression of SOCS1 was suppressed in renal tissues and peripheral blood mononuclear cells (PBMC) of IgAN patients, consistent with the results of dataset GSE35487. The expression of C1GALT1 in PBMC from IgAN patients was decreased and positively correlated with SOCS1 expression, while the expressions of TLR9 and MyD88 were increased and negatively correlated with SOCS1 expression. In vitro, SOCS1 overexpression inhibited the secretion of IgA1 and galactose-deficient IgA1 (Gd-IgA1) in DAKIKI cells, as well as the expression of TLR9. Knockdown of SOCS1 had the opposite effect. As a negative regulator of TLR9, SOCS1 inhibited the expression of TLR9, thereby preventing aberrant IgA galactosylation. MyD88 knockdown restored the CpG-ODN (TLR9 ligand)-induced overproduction of IgA1 and Gd-IgA1, and the reduction of C1GALT1. In vivo experiments demonstrated that SOCS1 significantly inhibited the production of aberrant glycosylated IgA IgG-IgA immune complexes and IL-6 in mice, reduced glomerular IgA, IgG, and C3 deposition and tethered cell proliferation, and alleviated renal injury. Decreased expression of SOCS1 contributes to IgAN pathogenesis by promoting aberrant IgA galactosylation via activating TLR9/MyD88 pathway. Our study may provide a prospective treatment target for IgAN.