Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026
Dicer-independent miR-451a is upregulated in periodontitis and potentiates inflammation by impairing macrophage polarization and SOCS activity.
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Naqvi Raza Ali, Maddalozzo Jack, Amin Kreena, Capistrano Kristelle, Valverde Araceli, Rahat Rani, Siddiqui Hasan, Li Wei, Wu Christine D, Zhang Shaoping, Pettiette Mary, Moretti Antonio, Singh Gatikrushna, Nares Salvador, Naqvi Afsar
Аннотация
BACKGROUND: Periodontitis (PD) is characterized by localized inflammatory tissue destruction, yet the lesion-associated microRNA (miRNA)networks that regulate host immune responses remain incompletely defined. In this study, we aimed to identify and characterize dysregulated gingivalmiRNAs in PD that modulate inflammatory responses.
METHODS: Using a split-mouth design, miRNA expression was profiled in gingival biopsies fromperiodontal lesions and clinically healthy sites. Differentially expressed miRNAs were identified by microarray analysis, and selected candidates werevalidated by RT-qPCR. The responses of candidate miRNAs to periodontal bacterial challenge were evaluated, followed by functional studies ofmacrophage polarization, phagocytosis, inflammatory cytokine production, and target-gene regulation.
RESULTS: Microarray analysis identified 48differentially expressed miRNAs, including several upregulated non-canonical miRNAs. Among these, the Dicer-independent miRNAs miR-451a andmiR-1228 showed dose- and time-dependent induction following periodontal bacterial challenge. miR-451a, but not miR-1228, promoted a pro-inflammatory M1-like macrophage phenotype, characterized by increased HLA-DR and CD32 and reduced CD206 and CD163 expression. miR-451adirectly targeted multiple genes associated with M2 macrophage polarization, and its expression in inflamed gingival tissues inversely correlated with M2markers. miR-451a overexpression also reduced macrophage phagocytosis of E. coli and P. gingivalis while increasing pro-inflammatory cytokineproduction. Mechanistically, miR-451a directly suppressed SOCS3 and SOCS5, key negative regulators of JAK/STAT signaling, in TLR4-stimulated cells.The antagonistic expression patterns of miR-451a, SOCS3, and SOCS5 in PD further supported the functional relevance of this regulatory axis.
CONCLUSION: miR-451a is a pathogen-responsive, PD-associated miRNA that promotes pro-inflammatory macrophage polarization, impairs bacterialphagocytosis, and amplifies inflammation through suppression of SOCS-mediated immune regulation. These findings identify the miR-451a-SOCS3/SOCS5 axis as a potential mechanism linking bacterial challenge to dysregulated macrophage responses in PD.
METHODS: Using a split-mouth design, miRNA expression was profiled in gingival biopsies fromperiodontal lesions and clinically healthy sites. Differentially expressed miRNAs were identified by microarray analysis, and selected candidates werevalidated by RT-qPCR. The responses of candidate miRNAs to periodontal bacterial challenge were evaluated, followed by functional studies ofmacrophage polarization, phagocytosis, inflammatory cytokine production, and target-gene regulation.
RESULTS: Microarray analysis identified 48differentially expressed miRNAs, including several upregulated non-canonical miRNAs. Among these, the Dicer-independent miRNAs miR-451a andmiR-1228 showed dose- and time-dependent induction following periodontal bacterial challenge. miR-451a, but not miR-1228, promoted a pro-inflammatory M1-like macrophage phenotype, characterized by increased HLA-DR and CD32 and reduced CD206 and CD163 expression. miR-451adirectly targeted multiple genes associated with M2 macrophage polarization, and its expression in inflamed gingival tissues inversely correlated with M2markers. miR-451a overexpression also reduced macrophage phagocytosis of E. coli and P. gingivalis while increasing pro-inflammatory cytokineproduction. Mechanistically, miR-451a directly suppressed SOCS3 and SOCS5, key negative regulators of JAK/STAT signaling, in TLR4-stimulated cells.The antagonistic expression patterns of miR-451a, SOCS3, and SOCS5 in PD further supported the functional relevance of this regulatory axis.
CONCLUSION: miR-451a is a pathogen-responsive, PD-associated miRNA that promotes pro-inflammatory macrophage polarization, impairs bacterialphagocytosis, and amplifies inflammation through suppression of SOCS-mediated immune regulation. These findings identify the miR-451a-SOCS3/SOCS5 axis as a potential mechanism linking bacterial challenge to dysregulated macrophage responses in PD.