Interleukin-33 and RANK-L Interplay in the Alveolar Bone Loss Associated to Periodontitis

Introduction Chronic Periodontitis(CP) is an inflammatory disease of bacterial origin that results in alveolar bone destruction. Porphyromonas gingivalis(Pg), one of the main periopathogens, initiates an inflammatory cascade by host immune cells thereby increasing recruitment and activity of osteoclasts, the bone resorbing cells, through enhanced production of the crucial osteoclastogenic factor, RANK-L. Antibodies directed against some cytokines (IL-1β, IL-6 and TNF-α) failed to exhibit convincing therapeutic effect in CP. It has been suggested that IL-33, could be of interest in CP. Objective the present study aims to analyze whether and how IL-33 and RANK-L and/or their interplay are involved in the bone destruction associated to CP. Material and Methods mRNAs and protein expressions of IL-33 and RANK-L were analyzed in healthy and CP human gingivalsamples by immunohistochemistry (IHC) and RT-qPCR. Murine experimental periodontitis (EP) was induced using Pg infected ligatureand Pg free ligaturearound the first maxillary molar. Alveolar bone loss was recorded by μCT. Mouse gingivalexplants were stimulated for 24 hours with IL-33 and RANK-L mRNA expression investigated by RTqPCR. Human oral epithelial cells were infected by Pg for 6, 12; 24 hours and IL-33 and RANK-L mRNA expressions were analyzed by RT-qPCR. Results IL-33 is overexpressed in gingivalepithelial cells in human affected by CP as in the murine EP. In human as in murine gingivalcells, RANK-L was independently induced by Pg and IL-33. We also showed that the Pg-dependent RANK-L expression in gingivalepithelial cells occured earlier than that of IL-33. Conclusion Our results evidence that IL-33 overexpression in gingivalepithelial cells is associated with CP and may trigger RANK-L expression in addition to a direct effect of Pg. Finally, IL-33 may act as an extracellular alarmin (danger signal) showing proinflammatory properties in CP perpetuating bone resorption induced by Pg infection.