Extracellular RNA clearance by non-canonical cell-surface MDA5 protects against lung fibrosis

Abstract The role of innate immune receptors, specifically RNA sensors, in non-pathogen-driven lung fibrosis remains unclear. Here, we demonstrate that the cytosolic RNA sensor MDA5 could translocate to the cell surface upon bleomycin-induced damage. MDA5-deficient mice exhibited exacerbated lung fibrosis with increased IL-17A⁺ γδ T cells and neutrophils, which is independent of the canonical MAVS pathway and type I interferon signaling. Phenotypically, MDA5-deficient lung CD11b⁺ macrophages, which resemble human SPP1 ⁺ macrophages, showed elevated expression of CCR2 ligands. Mechanistically, cell-surface MDA5 acts as a scavenger receptor that captures extracellular self-RNA and shuttles it for lysosomal degradation. Loss of MDA5 leads to aberrant cellular RNA accumulation, triggering TLR8-dependent hyperproduction of CCR2 ligands. Analysis of human lung fibrosis samples from public datasets revealed SPP1 ⁺ macrophages are a major source of CCR2 ligands, suggesting their potential to activate monocytes. Our findings reveal an unrecognized protective function of MDA5 in lung fibrosis: preventing TLR8-mediated hyperinflammation through the lysosomal clearance of extracellular RNA. This mechanism provides crucial insights into the pathogenesis of fibrotic diseases like interstitial lung diseases.