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 GM-CSF-producing T cells that accumulates in the kidneys of patients with 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 licence monocyte-derived cells to produce matrix metalloproteinase 12 (MMP12), which cleaves components of the glomerular basement membrane and exacerbates renal pathology. These findings provide a mechanistic rationale for the immunopathology of T cell-mediated diseases and identify the "GM-CSF - monocyte-derived cells - MMP12" pathway as a promising therapeutic target in treatment of glomerulonephritis.