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

SUBMITTER: TAKASHI ISHII 

PROVIDER: S-SCDT-10_1038-S44321-026-00513-6 | biostudies-other |

REPOSITORIES: biostudies-other