Alternative Polyadenylation Drives Runaway Pro-Inflammatory Macrophages in Periodontitis by Enabling Escape From miRNA Repression

Abstract

Periodontitis is a chronic inflammatory disease driven by a dysregulated host immune response, in which macrophage-mediated inflammation shifts from protective to pathological. While monocyte-derived macrophages (MDMs) are known to adopt a destructive, M1-like pro-inflammatory phenotype, the mechanisms that enable this ‘runaway’ polarisation by bypassing endogenous negative feedback remain elusive. Here, we identify alternative polyadenylation (APA) as a critical post-transcriptional mechanism driven by pathogens to disrupt macrophage immune control. Integrating single cell RNA sequencing with Sierra APA analysis of human gingival tissues, we uncovered a global shift toward proximal poly(A) site (PAS) usage, indicative of 3′UTR shortening, specifically within the pro-inflammatory MDM subset. This APA remodelling preferentially affected genes essential for cytokine production and inflammatory signalling. In vitro, the keystone pathogen Porphyromonas gingivalis similarly induced widespread 3′UTR shortening in macrophages. This shortening systematically eliminated inhibitory miRNA-binding sites, thereby derepressing pro-inflammatory transcripts. Mechanistically, using Selenok as a representative example, we demonstrate that P. gingivalis induced 3′UTR shortening selectively abolishes repression by miR-320-3p, a ‘brake’ miRNA upregulated in periodontitis, whose binding site is excised by the proximal APA event. Collectively, these findings reveal APA remodelling as a key pathogenic strategy that enables pro-inflammatory macrophages to escape miRNA-mediated suppression, leading to an uncontrolled M1-like state. This ‘disruption’ of the post-transcriptional braking system provides a new mechanistic rationale for the persistent, destructive inflammation in periodontitis.

Keywords

alternative polyadenylation / macrophage polarisation / miRNA repression / periodontitis / post-transcriptional regulation

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2025 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.