A collaborative research effort involving the National Local Joint Engineering Research Center of Biomedical Diagnostics and Therapeutics, the International Cooperation Base of Cell Stress and Disease Diagnosis and Treatment, the Institute for Precision Medicine, and the School of Life Science and Technology at Xi'an Jiaotong University (XJTU), recently published a research paper titled Calhm6 governs macrophage polarization through Chp1-Camk4-Creb1 axis and ectosomal delivery in inflammatory responses in the high-impact international journal Advanced Science.

The study reveals the protective role of the calcium ion channel Calhm6, mediated by extracellular vesicle regulation of macrophages, in acute inflammation and tissue repair.

The team led by Geng Jing at XJTU's National Local Joint Engineering Research Center of Biomedical Diagnostics and Therapeutics has long been committed to studying the pathological mechanisms of innate immune cells in infection and inflammation-related diseases.

The team found that Calhm6, as a large-pore calcium ion channel, can mediate calcium ion influx and can be secreted by macrophages and encapsulated in extracellular vesicles (Ectosomes) under inflammatory stimulation.

After being internalized by environmental macrophages, it activates the Chp1-CaMK4-Creb1 signaling axis. This promotes the polarization of surrounding macrophages toward an M2-like phenotype, significantly alleviating systemic inflammation, acute lung injury, colitis, and drug-induced liver injury and promoting tissue repair.

Conversely, Calhm6 deficiency leads to Creb1 inactivation, causing macrophages to tend towards M1-like polarization, which, while enhancing bactericidal efficiency to some extent, significantly exacerbates tissue damage and raises mortality rates in mice in a sepsis model.

In addition, Geng's team also analyzed the transcriptional regulatory mechanism of Calhm6 expression, and found that under LPS/IFNγ stimulation, the transcription factor Irf1 can bind to the Calhm6 promoter and promote its expression; while IL-4 can activate Stat6, competitively inhibit the binding of Irf1, thereby downregulating Calhm6 expression.

This precise transcriptional regulation mechanism ensures that macrophages can accurately regulate the expression level of Calhm6 in different immune environments, avoiding loss of control of macrophage plasticity and maintaining immune homeostasis.

This study not only reveals a new function of Calhm6 in macrophage polarization and inflammation regulation but also identifies new potential targets for the precise treatment of inflammation-related diseases.