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bioRxiv · 10.1101/2023.02.01.526668

LncRNA MALAT1/microRNA-30b axis regulate macrophage polarization and function

Ahmad, I.·Naqvi, R.·Valverde, A.·Naqvi, A.
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Abstract

IntroductionMacrophages (M{varphi}) can polarize towards the proinflammatory M1 or proresolving M2 phenotype to control diverse biological processes such as inflammation, and tissue regeneration. Noncoding RNAs play critical roles in numerous biological pathways; however, their functional interaction in the regulation of M{varphi} polarization and immune responses remain unclear. ObjectivesTo examine relationship between lncRNA (MALAT1) and microRNA (miR-30b) in shaping macrophage polarization and immune functions. MethodsExpression of MALAT1 and miR-30b was examined in differentiating M1/M2 M{varphi}, human and murine inflamed gingival biopsies by RT-qPCR. MALAT1 and miR-30b direct interaction was examined by dual luciferase assays. Impact of MALAT1 knockdown and miR-30b overexpression was examined on macrophage polarization markers, bacterial phagocytosis, antigen uptake/processing and cytokine profiles. ResultsMALAT1 expression displays a time-dependent induction during M{varphi} differentiation and, upon challenge with TLR4 agonist (E. coli LPS). Knockdown of MALAT1 enhanced the expression of M2M{varphi} markers without affecting the M1M{varphi} markers, suggesting that MALAT1 favors the M1 phenotype by suppressing M2 polarization. MALAT1 knockdown M{varphi} exhibit reduced antigen uptake and processing, bacterial phagocytosis, and bactericidal activity, strongly supporting its critical role in regulating innate immune functions. Consistent with this, MALAT1 knockdown showed impaired cytokine secretion upon challenge with LPS. Importantly, MALAT1 exhibit an antagonistic expression pattern with all five members of the miR-30 family during M2M{varphi} differentiation. Dual-luciferase assays validated a novel sequence on MALAT1 that interacts with miR-30b, a microRNA that promotes the M2 phenotype. Phagocytosis and antigen processing assays unequivocally demonstrated that MALAT1 and miR-30b are functionally antagonistic. In human subjects with periodontal disease and murine model of ligature-induced periodontitis, we observed higher levels of MALAT1, and downregulation of miR-30b that correlates with higher M1M{varphi} markers expression in gingival tissues suggesting a pro-inflammatory function of MALAT1. ConclusionMALAT1/miR-30b antagonistic interaction shapes M{varphi} polarization in vitro and in inflamed gingival biopsies.

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Ahmad, I., Naqvi, R., Valverde, A., Naqvi, A.. 2023-02-03. LncRNA MALAT1/microRNA-30b axis regulate macrophage polarization and function. https://doi.org/10.1101/2023.02.01.526668

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