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Macrophages induce gingival destruction via Piezo1-mediated MMPs-degrading collagens in periodontitis.

ABSTRACT: Macrophages are an integral part of the innate immune response in periodontal tissue and play a crucial role in the progression of periodontitis. Here we reported that macrophages also provoke periodontitis-induced gingival destruction through Piezol-mediated collagen degradation. We discovered that the PIEZO1 expression was markedly elevated in patients with periodontitis through transcriptomic profiling. Moreover, Piezo1 promoted macrophage polarization toward the M1 type in response to lipopolysaccharide (LPS) and induced production of proinflammatory cytokines, which in turn stimulated production of matrix metalloproteinases (MMPs) leading to collagen degradation. Our study suggests that Piezol might be a potential therapeutic target for treating periodontitis-induced gingival destruction.

SUBMITTER: Zhao T

PROVIDER: S-EPMC10228731 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Macrophages induce gingival destruction via Piezo1-mediated MMPs-degrading collagens in periodontitis.

Zhao Tong T Chu Zhuangzhuang Z Chu Catherine Huihan CH Dong Shuo S Li Guoqing G Wu Jin J Tang Chunbo C

Frontiers in immunology 20230516

Macrophages are an integral part of the innate immune response in periodontal tissue and play a crucial role in the progression of periodontitis. Here we reported that macrophages also provoke periodontitis-induced gingival destruction through Piezol-mediated collagen degradation. We discovered that the <i>PIEZO1</i> expression was markedly elevated in patients with periodontitis through transcriptomic profiling. Moreover, Piezo1 promoted macrophage polarization toward the M1 type in response to ...[more]

PMID: 37261355

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Project description:Histone deacetylases (HDACs) are important regulators of gene expression that are aberrantly regulated in several inflammatory and infectious diseases. HDAC inhibitors (HDACi) suppress inflammatory activation of various cell types through epigenetic and non-epigenetic mechanisms, and ameliorate pathology in a mouse model of periodontitis. Activation of gingival fibroblasts (GFs) significantly contributes to the development of periodontitis and the anaerobic bacterium Porphyromonas gingivalis plays a key role in driving chronic inflammation. Here, we analyzed the role of HDACs in inflammatory responses of GFs. Pan-HDACi suberoylanilide hydroxamic acid (SAHA) and/or ITF2357 (givinostat) significantly reduced TNFα- and P. gingivalis-inducible expression and/or production of a cluster of inflammatory mediators in healthy donor GFs (IL1B, CCL2, CCL5, CXCL10, COX2, and MMP3) without affecting cell viability. Selective inhibition of HDAC3/6, but not specific HDAC1, HDAC6, or HDAC8 inhibition, reproduced the suppressive effects of pan-HDACi on the inflammatory gene expression profile induced by TNFα and P. gingivalis, suggesting a critical role for HDAC3 in GF inflammatory activation. Consistently, silencing of HDAC3 expression with siRNA largely recapitulated the effects of HDAC3/6i on mRNA levels of inflammatory mediators in P. gingivalis-infected GFs. In contrast, P. gingivalis internalization and intracellular survival in GFs remained unaffected by HDACi. Activation of mitogen-activated protein kinases and NFκB signaling was unaffected by global or HDAC3/6-selective HDACi, and new protein synthesis was not required for gene suppression by HDACi. Finally, pan-HDACi and HDAC3/6i suppressed P. gingivalis-induced expression of IL1B, CCL2, CCL5, CXCL10, MMP1, and MMP3 in GFs from patients with periodontitis. Our results identify HDAC3 as an important regulator of inflammatory gene expression in GFs and suggest that therapeutic targeting of HDAC activity, in particular HDAC3, may be clinically beneficial in suppressing inflammation in periodontal disease.

Project description:Background: Irradiation disrupts the vascular niche where hematopoietic stem cells (HSCs) reside, causing delayed hematopoietic reconstruction. The subsequent recovery of sinusoidal vessels is key to vascular niche regeneration and a prerequisite for hematopoietic reconstruction. We hypothesize that resident bone marrow macrophages (BM-Mφs) are responsible for repairing the HSC niche upon irradiation injury. Methods: We examined the survival and activation of BM-Mφs in C57BL/6 mice upon total body irradiation. After BM-Mφ depletion via injected clodronate-containing liposomes and irradiation injury, hematopoietic reconstruction and sinusoidal vascular regeneration were assessed with immunofluorescence and flow cytometry. Then enzyme-linked immunosorbent assay (ELISA) and flow cytometry were performed to analyze the contribution of VEGF-A released by BM-Mφs to the vascular restructuring of the HSC niche. VEGF-A-mediated signal transduction was assessed with transcriptome sequencing, flow cytometry, and pharmacology (agonists and antagonists) to determine the molecular mechanisms of Piezo1-mediated responses to structural changes in the HSC niche. Results: The depletion of BM-Mφs aggravated the post-irradiation injury, delaying the recovery of sinusoidal endothelial cells and HSCs. A fraction of the BM-Mφ population persisted after irradiation, with residual BM-Mφ exhibiting an activated M2-like phenotype. The expression of VEGF-A, which is essential for sinusoidal regeneration, was upregulated in BM-Mφs post-irradiation, especially CD206+ BM-Mφs. The expression of mechanosensory ion channel Piezo1, a response to mechanical environmental changes induced by bone marrow ablation, was upregulated in BM-Mφs, especially CD206+ BM-Mφs. Piezo1 upregulation was mediated by the effects of irradiation, the activation of Piezo1 itself, and the M2-like polarization induced by the phagocytosis of apoptotic cells. Piezo1 activation was associated with increased expression of VEGF-A and increased accumulation of NFATC1, NFATC2, and HIF-1α. The Piezo1-mediated upregulation in VEGF-A was suppressed by inhibiting the calcineurin/NFAT/HIF-1α signaling pathway. Conclusion: These findings reveal that BM-Mφs play a critical role in promoting vascular niche regeneration by sensing and responding to structural changes after irradiation injury, offering a potential target for therapeutic efforts to enhance hematopoietic reconstruction.

Dataset Information

Macrophages induce gingival destruction via Piezo1-mediated MMPs-degrading collagens in periodontitis.

Publications

Macrophages induce gingival destruction via Piezo1-mediated MMPs-degrading collagens in periodontitis.

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