CD300a Blockade attenuates renal fibrosis by enhancing macrophage efferocytosis and neutrophil MMP9 production

Renal fibrosis marks an irreversible stage of chronic kidney disease. While macrophage efferocytosis aids in responding to acute kidney injury, the ways early efferocytosis provides long-term protection against chronic fibrosis are unclear. Researchers discovered that deleting the inhibitory receptor CD300a (Cd300afl/flLyz2-Cre) in phagocytes helps prevent obstructive renal injury and later fibrosis.

When CD300a was missing, tissue-resident macrophages improved efferocytosis in the early injury stage. This early efferocytosis reduction of damage-associated molecular patterns (DAMPs) and TGF-β expression controlled the inflammatory environment. Consequently, recruited neutrophils shifted from profibrotic SiglecF+ subsets to non-profibrotic SiglecF- subsets.

Moreover, eliminating CD300a directly prepared neutrophils to produce increased matrix metalloproteinase-9 (MMP9) upon injury. However, removing neutrophils stopped the protective effect of CD300a deficiency. Notably, using a neutralizing anti-CD300a antibody in healthy mice duplicated these protective effects, promoting the shift to SiglecF- neutrophils and significantly reducing renal fibrosis.

Overall, the study identifies CD300a as a factor influencing early macrophage efferocytosis and neutrophil-derived MMP9 production, suggesting that pharmacological CD300a blockade could be a potential therapy for advanced renal fibrosis.