Periopathogens Modulate Inflammation by Repressing miR-142-3p and Augmenting miR-155/NFκB axis

• Published in: The Journal of immunology (1950) 2022-05, Vol.208 (1_Supplement), p.111-111.17
• Main Authors: Valverde, Araceli Maria, Schaller, Samantha, Brandini, Daniela Atili, Brambila, Maria F., Martinez, Gloria, Chapa, Gabriela, Li, Wei, Wu, Christine, Rahat, Rani, Siddiqui, Hasan, Nares, Salvador, Naqvi, Afsar
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.208.Supp.111.17

MicroRNA (miR) play a critical role in the pathogenesis of immune-mediated diseases. We hypothesize that periopathogens (P. gingivalis [Pg] and A. actinomycemtemcomitans [Aa]) impair host immune response by perturbing miR expression. Periopathogen burden, cytokine and miR expression was quantified by qPCR in healthy and inflamed human gingival biopsies. Human primary CD14+ monocytes were differentiated to M1 or M2 macrophages (MΦ) and challenged with live Pg or Aa to monitor expression profiles of pro- and anti-inflammatory miRs by qPCR. Supernatant levels of cytokines were assessed by multiplex bead assay while, protein levels were quantified by western blot. Murine gingival miRNA and mRNA profiles were validated during disease progression in a liguture-induced periodontitis model and bone loss measured by microCT. Higher periopathogen burden and inflammatory cytokine expression was observed in inflamed gingiva with a higher expression of pro-inflammatory miR-155 and reduced levels of anti-inflammatory miR-142-3p. This corroborates with NFκB activation and downregulation of PU.1 suggesting a distinct role of a miR and transcription factor (TF) axis. miR-155-mediated downregulation of PU.1, a TF of miR-142, suppressed transcription of miR-142, thereby alleviating silencing of IL-6 mediated by miR-142-3p. Our murine ligature model showed progressive bone loss in the presence of Pg and higher expression of cytokine profiles. Local delivery of miR-142-3p showed reduction in IL-6. Periopathogen-mediated activation of miR-155/NFκB axis augments inflammatory signaling by decreasing levels of PU.1 and expression of its target miR-142. This mechanism may be critical in the pathogenesis of periodontal disease. Supported by R01 DE027980, R21 DE026259, R03 DE027147