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Dysregulation of CXCL1 expression and neutrophil recruitment in insulin resistance and diabetes-related periodontitis in male mice

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posted on 2023-04-14, 17:20 authored by Takanori Shinjo, Satoru Onizuka, Yumi Zaitsu, Atsushi Ishikado, Kyoungmin Park, Qian Li, Hisashi Yokomizo, Tatsuro Zeze, Kohei Sato, Ronald St-Louis, Jialin Fu, Wu I-Hsien, Koji Mizutani, Hatice Hasturk, Thomas E Van Dyke, Fusanori Nishimura, George L King

  

Insulin resistance and hyperglycemia are risk factors for periodontitis and poor wound healing in diabetes, which have been associated with selective loss of insulin- activation of the PI3K/Akt pathway in the gingiva. This study showed that insulin resistance in the mouse gingiva due to selective deletion of smooth muscle and fibroblast insulin receptor (SMIRKO mice) or systemic metabolic changes induced by high fat diet (HFD) in HFD-fed mice exacerbated periodontitis-induced alveolar bone loss, preceded by delayed neutrophil and monocyte recruitment and impaired bacterial clearance compared to their respective controls. The immunocytokines, CXCL1, CXCL2, MCP-1, TNFα, IL-1β and IL-17A exhibited delayed maximal expression in the gingiva of male SMIRKO and HFD-fed mice compared to controls. Targeted overexpression of CXCL1 in the gingiva by adenovirus normalized neutrophil and monocyte recruitment and prevented bone loss in both mouse models of insulin resistance. Mechanistically, insulin enhanced bacterial lipopolysaccharide-induced CXCL1 production in mouse and human gingival fibroblasts (GFs), via Akt pathway and NF-κB activation, which were reduced in GFs from SMIRKO and HFD-fed mice. These results provided the first report that insulin signaling can enhance endotoxin induced CXCL1 expression to modulate neutrophil recruitment, suggesting CXCL1 as a new therapeutic direction for periodontitis or wound healing in diabetes. 

Funding

T.S. is the recipient of research fellowships (Hiroo Kaneda Scholarship, Sunstar Foundation, Japan and Mary K. Iacocca Foundation). Support was also provided by the NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Diabetes Research Center grant R01 DK053105 to G.L.K.

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