IFNAR1+ Neutrophils Orchestrate Chronic Inflammatory Damage Through Mitochondrial Remodeling

Neutrophils are abundant innate effector cells that drive mucosal inflammation, yet the mechanisms by which they contribute to chronic inflammatory diseases across distinct tissues remain incompletely understood. Here, by reanalyzing single-cell RNA-seq datasets from patients with inflammatory bowel disease (IBD) and chronic obstructive pulmonary disease (COPD), we identify a shared neutrophil activation program enriched for type I interferon (IFN) signaling, nuclear factor-{kappa}B (NF-{kappa}B) and AP-1 transcriptional regulators, and effector pathways including NETosis, degranulation, and leukocyte trafficking. To interrogate these signatures, we established a CRISPR-compatible neutrophil differentiation platform from adult CD34 progenitors, which yielded cells closely resembling primary neutrophils at transcriptomic, proteomic, and functional levels. A targeted CRISPR-Cas9 screen revealed a central role for the mitochondrial iron transporter mitoferrin-1 (SLC25A37) in coordinating neutrophil oxidative phosphorylation, NET formation, and type I IFN production downstream of TLR9. Mechanistically, we show that NET-derived citrullinated histones activate an autocrine IFN-IFNAR1 loop, amplifying neutrophil inflammatory functions without impairing phagocytosis. Disruption of this loop, through IFNAR1 depletion or blockade, dampened neutrophil-driven tissue damage in human intestinal and alveolar organoid co-cultures as well as in murine models of colitis and cigarette smoke-induced lung inflammation. These findings uncover a conserved IFN-driven metabolic circuit in neutrophils that underpins pathology across chronic mucosal diseases and identify IFNAR1 as a therapeutic node to selectively disarm neutrophil-mediated tissue injury.