IFNAR1-dependent metabolic circuit drives pathogenic neutrophil activation in chronic mucosal inflammation
TL;DR
A conserved IFNAR1-driven circuit mediated by iron homeostasis that sustains neutrophil pathogenicity across distinct mucosal tissues is defined and a targetable metabolic node for selectively disarming pathogenic neutrophil responses in the setting of chronic inflammatory disease is identified.
Abstract
Neutrophils are double-edged effectors of the innate immune system: while essential for host defense, they can drive significant tissue damage in the context of chronic inflammatory diseases. Identifying strategies to selectively dampen their pathogenic functions without compromising antimicrobial immunity remains a major clinical challenge. Here, we define a conserved IFNAR1-driven circuit mediated by iron homeostasis that sustains neutrophil pathogenicity across distinct mucosal tissues. Using single-cell transcriptomics and a CRISPR-based functional screen, we identified the mitochondrial iron transporter Mitoferrin-1 (SLC25A37) as a key regulator of neutrophil inflammatory programming. Mechanistically, our data indicate that Mitoferrin-1 mediates a feedforward loop in which NET-derived histones activate toll-like receptor 9 (TLR9), which in turn sustains IFN-α/IFNAR1 signaling, rewires mitochondrial metabolism, and ultimately drives tissue damage through markedly increased of NETosis, reactive oxygen species production, and degranulation. Notably, this IFNAR1-driven inflammatory circuit operates entirely independently of antimicrobial function, as pharmacological IFNAR1 blockade fully preserves phagocytic activity against bacterial pathogens in vivo. Targeting this pathway selectively attenuates neutrophil-driven inflammation in both murine models of colitis and acute lung injury, as well as in primary human intestinal organoid systems. Together, these findings identify a targetable metabolic node for selectively disarming pathogenic neutrophil responses in the setting of chronic inflammatory disease.