The accumulation of reactive oxygen species (ROS) leads to enhanced osteoclast activity, causing severe bone destruction in postmenopausal osteoporosis. Immunity-related GTPase family M member 1 (Irgm1) plays an essential role in affecting the production of intracellular ROS. To detect whether deletion of Irgm1 could suppress osteoclastogenesis through cellular redox regulation, we first evaluated whether the Irgm1 level was significantly elevated in mice bone marrow-derived monocytes/macrophages (BMDMs) from ovariectomy (OVX)-induced osteoporosis mice. Moreover, bioinformatics network analysis was performed to identify Irgm1 as a key upregulated gene during osteoclast differentiation. Next, we found that macrophage-specific Irgm1 knockout (Irgm1-cKO, Lyz2-Cre; Irgm1 flox/flox ) in OVX mice resulted in slower bone loss compared with OVX mice from the control group (Irgm1 flox/flox ). We then demonstrated that loss of Irgm1 inhibited osteoclast differentiation and bone resorption function via suppressing ROS accumulation. Further mechanism revealed that Irgm1 could endogenously bind to kelch-like ECH-associated protein 1 (Keap1) and keep Keap1 from ubiquitination and degradation. In the absence of Irgm1, Keap1 was downregulated and causing nuclear factor erythroid 2-related factor 2 (Nrf2) to translocate to the nucleus, thereby activating the level of the antioxidant system to combat oxidative stress. Moreover, Irgm1 deficiency in RAW264.7 promoted osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) through inhibiting the M1 phenotype polarization. Taken together, our results revealed that loss of Irgm1 significantly alleviates OVX-induced bone loss, thus laying the foundation for exploring Irgm1 as a novel targeting approach for the treatment of osteoporosis.
Delayed neutrophil clearance after myocardial infarction (MI) significantly disrupts the myocardial microenvironment, but the underlying mechanisms remain unclear. Macrophage-mediated efferocytosis of infiltrating neutrophils is crucial for resolving inflammation and restoring homeostasis post-MI. However, the specific regulatory mechanisms governing neutrophil clearance and efferocytosis remain undefined. This study demonstrates a significant correlation between increased IRGM expression in peripheral blood neutrophils of patients with MI and improved prognostic outcomes. Neutrophil-specific deletion of Irgm1 exacerbates cardiac dysfunction, impairs post-MI repair, and hinders neutrophil clearance and efferocytosis. Irgm1 deficiency further delays neutrophil clearance in the heart and extends neutrophil survival. Mechanistically, Irgm1 directly interacts with PDIA3, promoting its autophagic degradation, which in turn activates the endoplasmic reticulum stress/NF-κB/caspase-3 pathway to facilitate neutrophil clearance and efferocytosis. In vivo administration of LOC14 significantly reduces tissue damage and enhances cardiac recovery in neutrophil Irgm1-deficient mice post-MI. These findings highlight the pivotal role of the Irgm1-PDIA3 axis in facilitating cardiac repair post-MI by promoting neutrophil clearance. LOC14 may serve as a potential therapeutic agent to enhance cardiac function post-MI, particularly in Irgm1-deficient cases.
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