Calhm6: A Gatekeeper of Macrophage Plasticity and Immune Response [Raw264.7-OE]

The dysregulation of macrophage differentiation is a significant contributing factor to the development of infection, inflammation, and even tumors. However, there are still numerous uncertainties surrounding the mechanism by which macrophage plasticity is controlled. Here, we report that Calhm6 regulates macrophage plasticity in a bidirectional negative feedback way to maintain host defense and tissue homeostasis. Specifically, the deficiency of Calhm6 greatly enhances the expression of pro-inflammatory mediators, bactericidal activity, and the M1-like differentiation of macrophages. Mechanistically, the accumulation of Calhm6 and intracellular calcium was increased by LPS-IFNγ through Irf1, which made M1-like signal turn off and weakened bactericidal activity. Instead, the IL-4 signal inhibits the transcription of Calhm6 via Stat6, preventing macrophages from over-differentiating into M2-like cells. Additionally, we have identified a distinct isoform of Calhm6, which exhibits contrasting functionality compared to the full-length of Calhm6. Furthermore, both full-length or isoform of Calhm6 can be released into the extracellular or serum through ectosomes, thereby exerting a systemic influence on the differentiation and plasticity of macrophages in host. Overall, our work reveals the mechanism of calcium-driven Calhm6 in regulating the host defense and tissue homeostasis of macrophages, and provides ectosomes wrapped with Calhm6 as a therapeutic agent to improve anti-infection and tissue repair.