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

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 Ly6C^hi 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⁺Ly6C^hi 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.