Dicer-independent miR-451a is Upregulated in Periodontitis and Potentiates Inflammation by Impairing Macrophage Polarization and SOCS Activity

Abstract Periodontitis is characterized by localized inflammatory tissue destruction, yet the lesion-specific microRNA networks that shape host immune responses remain incompletely defined. Using a split-mouth design, we profiled miRNA expression in gingival biopsies obtained from periodontal lesions and clinically healthy sites within the same individuals to identify disease-associated regulatory signatures. Microarray analysis revealed 48 differentially expressed miRNAs, including several upregulated non-canonical species, and selected candidates were validated by RT-qPCR. Among these, the Dicer-independent miRNAs miR-451a and miR-1228 showed dose- and time-dependent induction in response to periodontal bacterial challenge. Functional studies demonstrated that miR-451a, but not miR-1228, promoted a pro-inflammatory M1-like macrophage phenotype, characterized by increased HLA-DR and CD32 expression and reduced CD206 and CD163. Consistent with this, miR-451a directly targeted multiple genes associated with M2 polarization, and its expression in inflamed gingival tissues inversely correlated with M2 marker expression. Moreover, miR-451a overexpression impaired bacterial phagocytosis and enhanced inflammatory cytokine production. Mechanistically, miR-451a suppressed SOCS3 and SOCS5, key negative regulators of JAK/STAT signaling, in TLR4-stimulated cells. Collectively, these findings identify miR-451a as a pathogen-responsive, periodontitis-associated miRNA that reprograms macrophage polarization, weakens antibacterial defense, and amplifies inflammation through suppression of SOCS-mediated immune regulation.