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. The innate immune receptor MDA5 plays a protective role in non-pathogen-driven lung fibrosis. By translocating to the cell surface, MDA5 clears damage-induced extracellular self-RNA via lysosomal degradation, preventing fatal hyperinflammation and fibrotic disease. Upon bleomycin-induced cellular damage, cytosolic MDA5 is dynamically translocated to the plasma membrane to function as a cell-surface scavenger receptor. Extracellular self-RNA is actively captured by surface MDA5 and shuttled into the lysosomal degradation pathway to prevent abnormal tissue accumulation. In MDA5-deficient models, accumulated extracellular RNA is aberrantly recognized by TLR8, whereby pathological hyperinflammation and exacerbated lung fibrosis are triggered. The hyperproduction of CCR2 ligands by SPP1+ macrophages and distinct IFIH1 expression in BALF cells and lungs are identified in human interstitial lung diseases. Upon bleomycin-induced cellular damage, cytosolic MDA5 is dynamically translocated to the plasma membrane to function as a cell-surface scavenger receptor. Extracellular self-RNA is actively captured by surface MDA5 and shuttled into the lysosomal degradation pathway to prevent abnormal tissue accumulation. In MDA5-deficient models, accumulated extracellular RNA is aberrantly recognized by TLR8, whereby pathological hyperinflammation and exacerbated lung fibrosis are triggered. The hyperproduction of CCR2 ligands by SPP1+ macrophages and distinct IFIH1 expression in BALF cells and lungs are identified in human interstitial lung diseases. The innate immune receptor MDA5 plays a protective role in non-pathogen-driven lung fibrosis. By translocating to the cell surface, MDA5 clears damage-induced extracellular self-RNA via lysosomal degradation, preventing fatal hyperinflammation and fibrotic disease.