Calhm6 Governs Macrophage Polarization Through Chp1‐Camk4‐Creb1 Axis and Ectosomal Delivery in Inflammatory Responses

Abstract Macrophage plasticity, critical for immune response, is often dysregulated in various infectious and inflammatory diseases. While ion channels have been implicated in immune cell modulation, how they influence macrophage polarization remains poorly understood. Here, it is demonstrated that ectosomes carrying the ion channel Calhm6 effectively suppress severe inflammation triggered by LPS. These Calhm6‐bearing ectosomes, secreted by macrophages, facilitate M2‐like polarization, elicit an anti‐inflammatory response, and foster immune tolerance. Conversely, Calhm6 deficiency leads to suppressed Creb1 activity, which in turn augments M1‐like macrophage polarization, enhancing bactericidal activity and the secretion of pro‐inflammatory cytokines. Mechanistically, Chp1 serves as a scaffold protein and undergoes phosphorylation by CaMK4. This phosphorylation enhances the localization of the Calhm6‐Chp1‐CaMK4 complex to the cell membrane, promoting Creb1 activation and M2‐like macrophage polarization calcium‐dependently. Moreover, the M1‐like polarization inducers LPS and IFNγ enhance the binding of Irf1 to the Calhm6 promoter, upregulating its expression and stimulating ectosome formation. Conversely, Stat6, activated by IL‐4, competes with Irf1 for binding to the Calhm6 promoter, thereby suppressing its expression. In summary, our findings unravel the intricate interplay between ion channels, ectosomes, and macrophage polarization, revealing that ectosomal‐Calhm6 can serve as a novel therapeutic agent to modulate inflammatory responses and facilitate tissue repair.