Huang Yanru, Wang Qinghai, Lin Chunqin, Qiu Bingbing, Chen Shulian, Wang Jianxin
Department of Pediatrics, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, 362000, Fujian Province, China.
Immunol Res. 2025 Aug 4;73(1):115. doi: 10.1007/s12026-025-09669-8.
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.
IgA异常糖基化是IgA肾病（IgAN）发病的核心因素。细胞因子信号转导抑制因子1（SOCS1）的表达与IgAN患者的IgA1分泌呈负相关，且Toll样受体9（TLR9）/髓样分化因子88（MyD88）促进异常糖基化IgA的形成。因此，本研究通过体内和体外实验探讨SOCS1是否通过调节TLR9/MyD88信号通路参与IgAN中IgA的异常糖基化。利用生物信息学分析和免疫荧光分析IgAN患者和非IgAN患者中SOCS1的差异表达。采用IgAN小鼠模型和分泌IgA1的DAKIKI细胞模型验证SOCS1对IgAN中异常IgA糖基化的影响。此外，进行实时定量聚合酶链反应（qRT-PCR）、蛋白质免疫印迹法（western blot）和免疫组织化学实验，以揭示SOCS1对IgAN中TLR9/MyD88通路的调节作用。IgAN患者肾组织和外周血单个核细胞（PBMC）中SOCS1的表达受到抑制，这与数据集GSE35487的结果一致。IgAN患者PBMC中C1GALT1的表达降低，且与SOCS1表达呈正相关，而TLR9和MyD88的表达增加，与SOCS1表达呈负相关。在体外，SOCS1过表达抑制了DAKIKI细胞中IgA1和半乳糖缺乏型IgA1（Gd-IgA1）的分泌，以及TLR9的表达。敲低SOCS1则产生相反的效果。作为TLR9的负调节因子，SOCS1抑制TLR9的表达，从而防止IgA异常糖基化。敲低MyD88可恢复CpG-ODN（TLR9配体）诱导的IgA1和Gd-IgA1过量产生以及C1GALT1的降低。体内实验表明，SOCS1显著抑制小鼠中异常糖基化IgA、IgG-IgA免疫复合物和白细胞介素-6（IL-6）的产生，减少肾小球IgA、IgG和C3沉积以及系膜细胞增殖，并减轻肾损伤。SOCS1表达降低通过激活TLR9/MyD88通路促进IgA异常糖基化，从而导致IgAN发病。我们的研究可能为IgAN提供一个潜在的治疗靶点。
