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

ABSTRACT: 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.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE200880 | GEO | 2023/03/01

REPOSITORIES: GEO

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