Mechanisms of Chronic Inflammation in Periodontitis

National Institute Of Dental & Craniofacial Research

Investigators

Linked publications, trials & patents

Abstract

Our work in this period has particularly focused on the role of neutrophils in periodontitis. Neutrophil accumulation and activation have long been suspected as a culprits in periodontitis pathology. Additionally, inhibition of excessive neutrophil accumulation in animal models of periodontitis has led to protection from periodontal bone loss, allowing for experimental studies towards understanding of neutrophil-mediated mechanisms of disease. The overall objective of the study was to understand the role of NETs in periodontitis pathogenesis. NETs are extracellular mesh-like structures, made of a backbone DNA, decorated with intracellular and nuclear neutrophil proteins. Classic NET-associated proteins include histones (bearing distinct post-translational modifications such as citrullination and carbamylation), neutrophil elastase (NE) and myeloperoxidase. NETs are considered protective antimicrobial defenses; however, excessive NET formation has been linked to pathology in multiple disease models such as sepsis, thrombosis, atherosclerosis, and autoimmune disorders. NETs formation has been extensively documented in tissues and blood of patients of periodontitis. Our current work demonstrates a functional role for NETs in periodontitis and pinpoints NET- associated histones as mediators of disease pathology. In the ligature induced model of experimental periodontitis (LIP), we find accumulation of NETs early after disease induction. Critically, genetic or pharmacologic inhibition of NETosis as well as timely removal of NETs protects from disease associated Th17 inflammation and pathology. Interestingly, specific inhibition of extracellular histones also significantly prevents the induction of Il17 mediated inflammation and tissue destruction, suggesting a key role of NET- associated histones in the disease process. Finally, through clinical studies in patients with severe periodontitis patients, without confounding disease (such as RA), we document that levels of NET-associated histones with distinct post-translational modifications (citrullination and carbamylation) are significantly increased in tissues and peripheral blood of patients with periodontitis and that their levels correlate with disease severity, revealing clinical relevance of our experimental findings.