Work

The IL-33/ST2 Axis Promotes Traumatic Heterotopic Ossification by Driving Macrophage and Mast Cell-Mediated Inflammation via Autophagy Defects

Year: 2025

Type: article

Abstract: Trauma-induced Heterotopic ossification (tHO) is the abnormal osteogenesis occurring in soft tissues after traumatic musculoskeletal injury, which can lead to severe limb movement impairment or even disability. Recent studies have indicated that macrophages and mast cells play a crucial role in tHO, although their precise activation mechanism remained to be elusive. Here, we unveil a novel mechanism in which interleukin-33 (IL-33)-an alarmin in the mammalian innate immune response to trauma-rapidly increases upon tendon injury and binds to its receptor ST2 (IL-1RL1) on macrophages and mast cells. This binding initiates M2 polarization in macrophages and degranulation in mast cells, thereby promoting osteogenic differentiation during tHO formation. Mechanistically, the IL-33/ST2 axis leads to the autophagy defection in macrophages and mast cells. ST2-knockout (ST2-/-) markedly restores autophagy and mitigates tHO. Furthermore, we identified activation of the PI3K/AKT/mTOR pathway as a critical mechanism mediating IL-33-induced autophagy suppression. Restoration of autophagy via PI3K/AKT/mTOR pathway inhibitors similarly counteracts the aberrant osteogenic healing effects induced by IL-33. To explore a therapeutic strategy, we fabricated a bacterial cellulose (BC) hydrogel composite scaffold loaded with soluble ST2 (sST2), based on a competitive inhibition approach. These scaffolds successfully sequestered IL-33 during the early inflammatory phase, thereby alleviating macrophage- and mast cell-mediated inflammation and tHO formation. By identifying overexpression of the IL-33/ST2 axis in human HO tissues and further validating through animal experiments, this study elucidates how the alarmin IL-33 contributes to tHO via immune regulation. Our findings reinforce the pivotal role of autophagy in attenuating HO and provide new translational perspectives for its clinical treatment.

Source: International Journal of Biological Sciences

DOI: 10.7150/ijbs.122706