IL6-Dependent PIEZO1 Activation Promotes M1-Mediated Orthodontic Root Resorption via CXCL12/CXCR4.

Z H Zhang, R Zhu, Y Liu, F F Wang, A Y Jiang, R C Dan, Y H Liu, Y X Tang, J Liu, J Wang
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Abstract

Orthodontic root resorption (ORR) is a common yet significant complication of orthodontic treatment, largely driven by interactions between periodontal ligament cells (PDLCs) and M1 macrophages. Despite the clinical relevance of ORR, the role of mechanosensitive ion channels in PDLC-mediated ORR and the underlying mechanisms regulating inflammatory cell recruitment remain poorly understood. Here, we identified PIEZO1 as a critical mechanosensitive ion channel that modulates monocyte recruitment and ORR. Using in vivo models treated with the PIEZO1 activator Yoda1 and inhibitor AAV-shPiezo1, we demonstrated that PIEZO1 activation promoted the recruitment of Ly6Chi inflammatory monocytes and exacerbated ORR. In contrast, PIEZO1 inhibition attenuated ORR and the accumulation of M1 macrophages. Mechanistically, PIEZO1 positively regulated the C-X-C motif chemokine 12 (CXCL12) and its receptor, C-X-C chemokine receptor type 4 (CXCR4). Blocking the CXCL12/CXCR4 axis using the CXCR4 antagonist AMD3100 significantly alleviated ORR, reversed M1 macrophage accumulation, and mitigated the recruitment of CD11b+Ly6Chi monocytes. Transwell migration assays with application of the PIEZO1 activator Yoda1 and PIEZO1 inhibitor GsMTX4 consistently confirmed the PIEZO1/CXCL12/CXCR4 axis as a key driver of PDLC-monocyte interactions. Notably, PIEZO1 overactivation was linked to excessive IL-6 production, and IL-6 deficiency inhibited the activation of PIEZO1 induced by Yoda1, leading to attenuation of ORR, M1 macrophage accumulation, and CXCL12/CXCR4 axis activation. Collectively, these findings reveal PIEZO1 in PDLCs as a pivotal modulator of inflammatory monocyte recruitment via the CXCL12/CXCR4 axis in ORR, with IL-6 playing an essential role in PIEZO1 activation. This study provides new insights into the molecular crosstalk between PDLCs and macrophages, offering potential therapeutic targets for mitigating ORR in orthodontic patients.

il6依赖性PIEZO1激活通过CXCL12/CXCR4促进m1介导的正畸根吸收。
正畸根吸收(ORR)是正畸治疗中一种常见但重要的并发症,主要由牙周韧带细胞(pdlc)和M1巨噬细胞之间的相互作用驱动。尽管ORR具有临床意义,但机械敏感离子通道在pdlc介导的ORR中的作用以及调节炎症细胞募集的潜在机制仍然知之甚少。在这里,我们确定PIEZO1是调节单核细胞募集和ORR的关键机械敏感离子通道。通过使用PIEZO1激活剂Yoda1和抑制剂AAV-shPiezo1处理的体内模型,我们证明了PIEZO1的激活促进了Ly6Chi炎症单核细胞的募集,并加剧了ORR。相反,PIEZO1抑制可以减弱ORR和M1巨噬细胞的聚集。在机制上,PIEZO1积极调节C-X-C基序趋化因子12 (CXCL12)及其受体C-X-C趋化因子受体4 (CXCR4)。使用CXCR4拮抗剂AMD3100阻断CXCL12/CXCR4轴可显著缓解ORR,逆转M1巨噬细胞积聚,并减轻CD11b+Ly6Chi单核细胞的募集。使用PIEZO1激活剂Yoda1和PIEZO1抑制剂GsMTX4进行的Transwell迁移实验一致证实了PIEZO1/CXCL12/CXCR4轴是pdlc -单核细胞相互作用的关键驱动因素。值得注意的是,PIEZO1的过度激活与过量的IL-6产生有关,IL-6缺乏抑制Yoda1诱导的PIEZO1的激活,导致ORR、M1巨噬细胞积累和CXCL12/CXCR4轴激活的衰减。总的来说,这些发现揭示了PIEZO1在pdlc中作为炎症单核细胞募集的关键调节剂,通过ORR中的CXCL12/CXCR4轴,IL-6在PIEZO1激活中发挥重要作用。这项研究为pdlc和巨噬细胞之间的分子串扰提供了新的见解,为减轻正畸患者的ORR提供了潜在的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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