Inflammatory myofibroblasts reprogram neutrophil fate to drive chronic inflammation in peri-implantitis

Abstract

Peri-implantitis (PI) is a multifactorial chronic inflammatory disease characterized by persistent mucosal inflammation and progressive marginal bone loss, yet the tissue architecture and cellular programs that sustain chronic inflammation remain incompletely defined. Here, we integrate single-cell and spatial transcriptomic analyses with targeted validation to map the PI microenvironment and its regulatory circuits. PI lesions exhibit marked immune enrichment, including expansion of CXCR4⁺ aged neutrophils with enhanced survival signaling consistent with apoptosis delay. Spatial and communication analyses reveal a PI-specific stromal–myeloid organization in which fibroblast-rich regions are closely associated with myeloid hotspots and display heightened CXCL- and CSF-related signaling. Within the fibroblast compartment, inflammatory myofibroblasts emerge as a prominent predicted source within a CXCL/CSF-enriched secretory program, with CXCL6 and CSF3 highlighted as candidate mediators of neutrophil recruitment and survival. Functionally, blockade of the CXCR2 axis reduces neutrophil infiltration and mitigates peri-implant bone resorption. Upstream regulatory analyses nominate STAT4 as a candidate upstream regulator of the inflammatory stromal program; pharmacologic perturbation with lisofylline reduces CXCL6/CSF3 expression, weakens neutrophil chemotaxis, partially restores apoptosis sensitivity, and alleviates inflammation and bone loss in vivo. Together, these findings support a stromal–neutrophil circuit that sustains chronic inflammation in PI and highlight stromal inflammatory programs and neutrophil recruitment/survival pathways as potential therapeutic entry points.

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Funding

Natural Science Foundation of Sichuan Province; No. 2025ZNSFSC0055. Research and Develop Program, West China Hospital of Stomatology, Sichuan University; No. LCYJ-ZD-202502

National Natural Science Foundation of China (National Science Foundation of China)(823B2018)

China Postdoctoral Science Foundation(GZC20251216)

Natural Science Foundation of Sichuan Province; No. 2026NSFSC1571.

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