CHAC2-mediated Glutathione Metabolic Reprogramming Drives N1 Polarization of Bone Marrow Neutrophils and Exacerbates Inflammatory Co-morbidities

The proinflammatory (N1) polarization of bone marrow (BM) neutrophils, driven by central immune remodeling in response to peripheral inflammation, plays a critical role in propagating localized inflammatory conditions, such as periodontitis, to systemic levels. Although this process involves metabolic reprogramming, the specific underlying metabolic mechanisms of neutrophil N1 polarization within the periodontitis-modified BM niche remain poorly defined. Integrated transcriptomic and metabolomic analyses in this study revealed that periodontitis reprograms intracellular glutathione (GSH) metabolism in BM neutrophils, facilitating their N1 polarization. Central to this mechanism is the upregulation of Chac2, an enzyme that promotes GSH accumulation. This enhancement is accompanied by elevated GSH redox cycling, which supports sustained ROS production and NET formation, thereby amplifying inflammatory responses. We further identified type I interferon (IFN-I) signaling as a key upstream regulator that induces Chac2 expression and drives metabolic reprogramming. Importantly, the intraosseous delivery of AAV-delivered Chac2 shRNA in db/db mice with periodontitis markedly reduced neutrophil-aggravated systemic inflammatory co-morbidity symptoms and improved glycemic control, underscoring the functional relevance of this pathway in diabetic co-morbidity. Together, these findings thus delineate the IFN-I–Chac2–GSH axis as a core signaling mechanism regulating neutrophil N1 polarization in the BM niche, providing new insights into how periodontal inflammation reprograms immune functions at the systemic level. This study thus broadens the conceptual framework of neutrophil immunometabolism and proposes targeting the Chac2–GSH axis as a potential therapeutic strategy for systemic comorbidities associated with periodontitis.