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This study aimed to explore whether macrophage pyroptosis plays a role in the development of diabetes mellitus\u2013periodontitis, as well as potential therapeutic strategies. By establishing a model of experimental diabetes mellitus\u2013periodontitis in rats, we found that IL-1\u03b2 and gasdermin D were highly expressed, leading to aggravated destruction of periodontal tissue. MCC950, a potent and selective molecule inhibitor of the NLRP3 inflammasome, effectively inhibited macrophage pyroptosis and attenuated alveolar bone losses in diabetes mellitus\u2013periodontitis. Consistently, in vitro, high glucose could induce macrophage pyroptosis and thus promoted IL-1\u03b2 production in macrophages stimulated by lipopolysaccharide. In addition, autophagy blockade by high glucose via the mTOR-ULK1 pathway led to severe oxidative stress response in macrophages stimulated by lipopolysaccharide. Activation of autophagy by rapamycin, clearance of mitochondrial ROS by mitoTEMPO, and inhibition of inflammasome by MCC950 could significantly reduce macrophage pyroptosis and IL-1\u03b2 secretion. Our study demonstrates that hyperglycemia promotes IL-1\u03b2 production and pyroptosis in macrophages suffered by periodontal microbial stimuli. Modulation of autophagy activity and specific targeting of the ROS-inflammasome pathway may offer promising therapeutic strategies to alleviate diabetes mellitus\u2013periodontitis.<\/jats:p>","DOI":"10.3390\/ijms24076309","type":"journal-article","created":{"date-parts":[[2023,3,28]],"date-time":"2023-03-28T02:11:40Z","timestamp":1679969500000},"page":"6309","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":64,"title":["Hyperglycemia Aggravates Periodontitis via Autophagy Impairment and ROS-Inflammasome-Mediated Macrophage Pyroptosis"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5039-2634","authenticated-orcid":false,"given":"Zhenxing","family":"Zhao","sequence":"first","affiliation":[{"name":"College of Stomatology, Chongqing Medical University, Chongqing 401147, China"},{"name":"Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China"},{"name":"Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Ming","sequence":"additional","affiliation":[{"name":"College of Stomatology, Chongqing Medical University, Chongqing 401147, China"},{"name":"Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China"},{"name":"Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Li","sequence":"additional","affiliation":[{"name":"College of Stomatology, Chongqing Medical University, Chongqing 401147, China"},{"name":"Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China"},{"name":"Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Tan","sequence":"additional","affiliation":[{"name":"College of Stomatology, Chongqing Medical University, Chongqing 401147, China"},{"name":"Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China"},{"name":"Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyi","family":"He","sequence":"additional","affiliation":[{"name":"College of Stomatology, Chongqing Medical University, Chongqing 401147, China"},{"name":"Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China"},{"name":"Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Stomatology, Chongqing Medical University, Chongqing 401147, China"},{"name":"Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China"},{"name":"Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinlin","family":"Song","sequence":"additional","affiliation":[{"name":"College of Stomatology, Chongqing Medical University, Chongqing 401147, China"},{"name":"Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China"},{"name":"Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leilei","family":"Zheng","sequence":"additional","affiliation":[{"name":"College of Stomatology, Chongqing Medical University, Chongqing 401147, China"},{"name":"Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China"},{"name":"Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1038\/nrendo.2011.106","article-title":"Diabetes mellitus and periodontitis: A tale of two common interrelated diseases","volume":"7","author":"Lalla","year":"2011","journal-title":"Nat. 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