A recent study revealed that periodontitis reprograms bone marrow neutrophils through a Chac2-driven glutathione metabolic pathway, promoting a highly inflammatory N1 state that fuels systemic inflammation, according to research published on Jul. 28.
Researchers used integrated transcriptomic, metabolomic, and animal studies to show that suppressing Chac2 reduced inflammatory responses and improved blood sugar control in diabetic mice. This finding highlights a promising therapeutic target for periodontitis-associated inflammatory comorbidities and other chronic inflammatory diseases linked to immune dysfunction in patients worldwide.
Chronic inflammatory diseases can affect organs beyond the original site of inflammation by reshaping immune responses throughout the body, a process called 'central immune remodeling.' The research team led by Prof. Xuliang Deng from Peking University School and Hospital of Stomatology investigated how periodontitis reprograms bone marrow neutrophils to promote systemic inflammation.
Lead author Prof. Deng said, "Our previous studies had shown an increase in BM neutrophil counts in response to periodontitis. These activated neutrophils released increased amounts of reactive oxygen species (ROS), formed neutrophil extracellular traps (NETs), and secreted pro-inflammatory cytokines, such as tumor necrosis factor-α, suggesting that they are of the inflammatory N1 phenotype." To uncover the metabolic mechanisms responsible for this transformation, researchers used mouse models of periodontitis and diabetes along with HL60 cell lines.
The study identified type I interferon signaling as an upstream regulator of Chac2 activation. Genetic experiments showed that disrupting IFN-I signaling prevented Chac2 activation and N1 polarization. Further tests using diabetic mice demonstrated that blocking Chac2 improved glycemic control and pancreatic function compared with untreated controls.
"To get benefits of our work out to every patient, we explored whether blocking Chac2 in the neutrophils could break this vicious chain," said Deng. The findings suggest targeting the IFN-I-Chac2-GSH pathway may offer new treatments for chronic conditions associated with periodontal disease.
