COVER STORY: Neutrophil Extracellular Traps (NETs) are elevated in human and murine fibrotic kidneys, correlating with functional decline in obstructive nephropathy. We demonstrate that NETs function as a critical regulator during renal fibrosis. They engage macrophage TLR2/4 receptors, triggering robust secretion of T-cell chemokines CXCL9, CXCL10, and CXCL11. These chemokines drive infiltration of cytotoxic CD8+ T cells into the renal parenchyma. Infiltrating CD8+ T cells release granzyme B (GZMB), directly promoting tubular epithelialmesenchymal transition (EMT) and fibroblast activation, key events in fibrosis pathogenesis. Genetic (PAD4 deletion) or pharmacological (DNase) NET inhibition, or GZMB blockade, significantly attenuated inflammation and fibrosis. This study defines a novel NETsmacrophage-CD8+ T cell axis orchestrating renal fibrogenesis.
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