TRIM30a coordinates neutrophil-macrophage crosstalk to resolve inflammation and drive osseointegration via suppressing NETosis/cGAS-STING axis

Jia Li; Yangbo Xu; Congrui Zhao; Xiaoyu Chen; Chuchu Xu; Chuan Zhou; Hui Wang; Antian Xu; Fuming He

doi:10.1016/j.mtbio.2025.102652

TRIM30a coordinates neutrophil-macrophage crosstalk to resolve inflammation and drive osseointegration via suppressing NETosis/cGAS-STING axis

Mater Today Bio. 2025 Dec 10:36:102652. doi: 10.1016/j.mtbio.2025.102652. eCollection 2026 Feb.

Authors

Jia Li^{1

2}, Yangbo Xu¹, Congrui Zhao¹, Xiaoyu Chen¹, Chuchu Xu¹, Chuan Zhou¹, Hui Wang¹, Antian Xu¹, Fuming He¹

Affiliations

¹ Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, Zhejiang, 310008, China.
² Department of Stomatology, School of Medicine, the First Affiliated Hospital of Xiamen University, Xiamen University, Xiamen, Fujian, 361003, China.

Abstract

The innate immune response to bone biomaterials critically regulates osteogenesis, yet the molecular mechanisms governing neutrophil-macrophage crosstalk remain poorly understood. Building on our discovery of neutrophil involvement in bone regeneration, we investigated the E3 ubiquitin ligase-Tripartite motif containing protein 30a (TRIM30a) as a potential orchestrator of inflammatory resolution and osseointegration. Through integrated multi-omics analysis of pro-osteogenic versus non-osteogenic metallic implants, we identified TRIM30a as a key regulator. Using conditional knockout mice (whole-body, neutrophil-specific, and macrophage-specific TRIM30a deficiency) combined with NETosis assays and inflammatory signaling profiling, we systematically evaluated TRIM30a's role on NETosis/cGAS-STING axis in bone regeneration, with pharmacological validation using DNase I in murine tibial implant models. TRIM30a expression was positively correlated with the osteogenic ability of pro-osteogenic implants. Mechanistically, TRIM30a suppressed NF-κB/NLRP3 signaling in neutrophils, while synergizing with NET-derived dsDNA to modulate cGAS-STING signaling in macrophages, thereby achieving balanced cytokine production. Therapeutic intervention with DNase I rescued bone formation in TRIM30a-deficient mice, confirming the clinical relevance of this pathway. Our work establishes TRIM30a as a master regulator of bone regeneration through dual mechanisms: restraining neutrophil hyperactivation via NF-κB/NLRP3 inhibition while cooperating with dsDNA to calibrate macrophage cGAS-STING signaling, revealing a targetable immunomodulatory axis for enhancing osseointegration. These findings provide new insights into the immune-bone regeneration interface and suggest novel therapeutic strategies for implant-related bone repair.

Keywords: Implant; Neutrophil extracellular traps; Osseointegration; TRIM30a.