Mechanisms of Chronic Inflammation in Periodontitis

National Institute Of Dental & Craniofacial Research

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Abstract

Our work in this period has particularly focused in the development of a single -cell transcriptome atlas of human oral mucosal tissues in health and in the setting of the common oral inflammatory disease periodontitis. This effort involved 29 human subject/volunteers and approximately 130K cells sequenced, with the intent of detailing cell populations and states in the oral mucosa in health and periodontitis. Our work details the complex landscape of oral mucosal cell types and provides comprehensive insights into cell functionality and disease susceptibility at this unique barrier. Our study is based on a meticulous characterization of patient cohorts with a strict definition of oral health and periodontal disease. Indeed, our healthy volunteer cohort was screened for medical history, medication, tobacco/alcohol/drug use and also evaluated through blood work and detailed oral examination. This study design has enabled the creation of an oral healthy atlas of true systemic and local (oral) health that can serve as a community resource towards understanding cell types and their functionality associated with oral mucosal tissue homeostasis. Our health cohort also serves as a normative baseline against which we can begin to explore changes in cell populations and their transcriptomes in the setting of oral tissue diseases. Furthermore, our evaluation of both tooth-associated (gingival) and lining (buccal) oral mucosa provides a baseline towards evaluation of diseases associated with these two distinct sites which typically present with unique disease susceptibilities of periodontitis. The atlas reveals a previously unappreciated diversity of immune, stromal and epithelial cells at the oral mucosa barrier. Furthermore, we document stromal and epithelial cell populations with immune functionality. In health, we characterize a gingiva-specific epithelial cell population as well as fibroblast populations expressing inflammatory mediators, particularly related to antimicrobial defense and neutrophil recruitment. Importantly, we find that stromal cells become particularly activated in the setting of periodontitis and stimulate immune cell recruitment and migration into disease lesions. In disease, fibroblasts and other stromal cells promote the specific recruitment of neutrophils but also express chemokines known to attract other leukocytes, including lymphocytes. These findings suggest a previously unacknowledged role for the mesenchymal compartment in immune responsiveness in oral homeostasis and disease pathogenesis. Collectively, our oral mucosal tissue atlas provides a comprehensive characterization of cell populations and states in health and periodontitis and provides insights into cell functionality and intercellular interactions in disease pathogenesis. Furthermore, our work reveals unique functionality of stromal cell populations participating in homeostatic immunity and inflammation at this barrier