Study reveals how gum disease drives systemic inflammation

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. Using integrated transcriptomic, metabolomic, and animal studies, researchers showed that suppressing Chac2 reduced inflammatory responses and improved blood sugar control in diabetic mice, highlighting 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 far beyond the original site of inflammation by reshaping immune responses throughout the body, a process known as 'central immune remodeling.' A research team led by Prof. Xuliang Deng from Peking University School and Hospital of Stomatology, China, investigated how periodontitis, a chronic inflammatory disease of the gums, reprograms bone marrow (BM) neutrophils to promote inflammation throughout the body.

Lead author Prof. Deng explains, "Our previous studies had shown 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 inflammatory transformation, the study, published in Volume 18 of the International Journal of Oral Science on July 9, 2026, used mouse models of periodontitis and diabetes, along with HL60 cell lines to investigate the molecular pathways driving N1 polarization of BM neutrophils.

The researchers first confirmed that periodontitis promoted N1 polarization in BM neutrophils. Metabolic analyses then revealed that glutathione (GSH) metabolism was the most strongly altered pathway. Further investigation identified Chac2, an enzyme involved in GSH regulation, as the key driver of this metabolic shift. Elevated Chac2 increased intracellular GSH levels, enhanced GSH redox cycling, sustained ROS production, promoted NET formation, and increased inflammatory cytokine expression, collectively reinforcing the N1 inflammatory phenotype. Experiments using Chac2-deficient HL60 cells further confirmed its central role in regulating GSH metabolism and neutrophil inflammatory polarization.

The team next investigated what triggered Chac2 activation. They identified type I interferon (IFN-I) signaling as the upstream regulator of this pathway. Genetic experiments using mice lacking the IFN-I receptor, along with Chac2-deficient HL60 cells, showed that disrupting IFN-I signaling prevented Chac2 activation, GSH metabolic reprogramming, and N1 polarization. These findings established the IFN-I- Chac2-GSH axis as a central mechanism linking localized periodontal inflammation to systemic immune remodeling.

To examine whether these immune changes affected other organs, the researchers used diabetic mice, a common inflammatory comorbidity associated with periodontitis. Compared with diabetic mice alone, those with periodontitis exhibited poorer glycemic control, impaired pancreatic function, and increased neutrophil infiltration into the pancreas. Furthermore, transferring neutrophils from mice with periodontitis into diabetic mice reproduced these effects, confirming that inflammatory BM neutrophils contributed directly to disease progression. Additional experiments showed that increasing GSH levels using glutathione diethyl ester worsened diabetes, whereas blocking GSH synthesis with L-buthionine sulfoximine improved glucose tolerance, further highlighting the importance of GSH metabolism in disease progression.

"To get benefits of our work out to every patient, we explored whether blocking Chac2 in the neutrophils could break this vicious chain," says Prof. Deng. The researchers therefore used an AAV9 vector to silence Chac2 in diabetic mice with periodontitis. After 3 weeks, these mice showed improved glycemic control and better pancreatic function than untreated controls.

Together, these findings identify the IFN-I- Chac2-GSH pathway as a key driver of systemic immune remodeling in periodontitis. By showing that Chac2 inhibition improves immune and metabolic outcomes, the study highlights a promising therapeutic target for periodontitis-associated comorbidities, including diabetes.