Affiliation:
1. Department of Orthopedic Changzheng Hospital Affiliated to Naval Medical University Shanghai 200003 China
2. State‐Key Laboratory of Chemical Engineering East China University of Science and Technology Shanghai 200237 China
3. Nation Key Laboratory of Medical Immunology Institute of Immunology Naval Medical University (Second Military Medical University) Shanghai 200433 China
4. Changzhou Hospital of Traditional Chinese Medicine Changzhou 213000 China
Abstract
AbstractThe effect of immunoinflammation on bone repair during the recovery process of bone defects needs to be further explored. It is reported that Mg2+ can promote bone repair with immunoregulatory effect, but the underlying mechanism on adaptive immunity is still unclear. Here, by using chitosan and hyaluronic acid‐coated Mg2+ (CSHA‐Mg) in bone‐deficient mice, it is shown that Mg2+ can inhibit the activation of CD4+ T cells and increase regulatory T cell formation by inducing immunosuppressive dendritic cells (imDCs). Mechanistically, Mg2+ initiates the activation of the MAPK signaling pathway through TRPM7 channels on DCs. This process subsequently induces the downstream HIF‐1α expression, a transcription factor that amplifies TGF‐β production and inhibits the effective T cell function. In vivo, knock‐out of HIF‐1α in DCs or using a HIF‐1α inhibitor PX‐478 reverses inhibition of bone inflammation and repair promotion upon Mg2+‐treatment. Moreover, roxadustat, which stabilizes HIF‐1α protein expression, can significantly promote immunosuppression and bone repair in synergism with CSHA‐Mg. Thus, the findings identify a key mechanism for DCs and its HIF‐1α‐TGF‐β axis in the induction of immunosuppressive bone microenvironment, providing potential targets for bone regeneration.