GM-CSF drives immune-mediated glomerular disease by licensing monocyte-derived cells to produce MMP12. GM-CSF drives immune-mediated glomerular disease by licensing monocyte-derived cells to produce MMP12

Glomerulonephritis is a group of immune-mediated diseases that cause inflammation within the glomerulus and adjacent compartments of the kidney and is a major cause of end-stage renal disease. T cells are among the main drivers of glomerulonephritis. However, the T cell subsets, cytokine networks, and downstream effector mechanisms that lead to renal tissue injury are largely unknown, which has hindered the development of targeted therapies. Here, we identify a population of granulocyte-macrophage colony-stimulating factor (GM-CSF)–producing T cells that accumulates in the kidneys of patients with antineutrophil cytoplasmic antibody (ANCA)–associated glomerulonephritis, infiltrates the renal tissue in a mouse model of glomerulonephritis, and promotes tissue destruction and loss of renal function. Mechanistically, we show that GM-CSF–producing T cells license monocyte-derived cells to produce matrix metalloproteinase 12 (MMP12), which cleaves components of the glomerular basement membrane and exacerbates renal pathology. Moreover, targeting GM-CSF or MMP12 reduced disease severity in mice with glomerulonephritis. Together, these findings provide a mechanistic rationale for the immunopathology of T cell–mediated diseases and identify this GM-CSF monocyte–derived cells–MMP12 axis as a promising therapeutic target for the treatment of glomerulonephritis. Overall design: Single cell sequencing of C57BL6 and Csf2-/- mice, single cell sequencing of patients

肾小球肾炎（Glomerulonephritis）是一类以肾小球及肾脏邻近结构发生炎症为特征的免疫介导性疾病，亦是终末期肾病的主要致病原因。T细胞是肾小球肾炎的核心驱动因素之一。然而，介导肾组织损伤的T细胞亚群、细胞因子网络及下游效应机制仍未完全明确，这一现状掣肘了靶向治疗的开发。本研究鉴定出一类可产生粒细胞-巨噬细胞集落刺激因子（granulocyte-macrophage colony-stimulating factor, GM-CSF）的T细胞群：该细胞群可在抗中性粒细胞胞浆抗体（antineutrophil cytoplasmic antibody, ANCA）相关性肾小球肾炎患者的肾脏中蓄积，在肾小球肾炎小鼠模型中浸润肾组织，并促进组织损伤与肾功能丧失。机制研究表明，产生GM-CSF的T细胞可诱导单核细胞衍生细胞产生基质金属蛋白酶12（matrix metalloproteinase 12, MMP12），后者可裂解肾小球基底膜组分，加重肾脏病理损伤。此外，靶向抑制GM-CSF或MMP12可减轻肾小球肾炎小鼠的疾病严重程度。综上，本研究的发现为T细胞介导性疾病的免疫病理机制提供了理论依据，并确定GM-CSF-单核细胞衍生细胞-MMP12轴作为治疗肾小球肾炎的潜在治疗靶点。整体实验设计：对C57BL/6小鼠及Csf2基因敲除（Csf2-/-）小鼠开展单细胞测序，同时对患者样本进行单细胞测序。