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

Sep 29, 2026

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Macrophage plasticity is dysregulated in infectious and inflammatory diseases, but the ion-channel mechanisms driving macrophage polarization remain unclear. Ectosomes carrying Calhm6 suppress severe LPS-triggered inflammation, promote M2-like polarization, induce anti-inflammatory signaling, and support immune tolerance. Calhm6 deficiency reduces Creb1 activity and enhances M1-like polarization, increasing bactericidal capacity and pro-inflammatory cytokines. Mechanistically, Chp1 scaffolding and CaMK4 phosphorylation enhance Calhm6 complex membrane localization, while Irf1/Stat6 promoter competition governs ectosome formation and polarity.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages23

Reading Time58 min

AccessFree to download

Introduction

Macrophage polarization and ion channels

Extracellular vesicles in infection and inflammation

CALHM6 characteristics and immune functions

RESEARCH ARTICLE [www.advancedscience.com](www.advancedscience.com) Calhm6 Governs Macrophage Polarization Through Chp1-Camk4-Creb1 Axis and Ectosomal Delivery in Inﬂammatory Responses Yanlong Xin, Xiaofan Xiong, Yan Zhang, Siyu Zhang, Shuting Zhang, Yu Yang, Yingxue Liang, Lulu Zang, Xi Chen, Wenjuan Li, Issam Halalmeh, Rui Zhou, Zongfang Li, Haowen Liu, and Jing Geng* 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 IFN􀀂 enhance the binding ofIrf1 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. 1. Introduction Macrophages play a pivotal role in the immune system’s early response to pathogen infections. They can polarize into distinct phenotypes, including M1-like (classically activated) and M2-like (alternatively activated) macrophages, each contributing to inﬂammation and infection defense or promoting tissue repair and immune tolerance. [1] Ion channels are crucial in the inﬂammatory process, not only by mediating cellular electrical signaling but also by regulating the balance of ions across cellular membranes. [2–4] Despite this, the precise mechanisms through which ion channels inﬂuence macrophage polarization and their responses to infection and inﬂammation remain poorly understood. [5–8] Extracellular vesicles, including exosomes and ectosomes, are essential for intercellular communication, particularly in the context of macrophage responses to infections and inﬂammation. Recent studies highlight the signiﬁcant role of exosomes in conditions such as sepsis and autoimmune diseases. [9,10] While exosomes and ectosomes are often considered functionally Y. Xin, X. Xiong, R. Zhou, Z. Li, J. Geng Department of General Surgery the Second Aﬃliated Hospital Xi’an Jiaotong University Xi’an 710004, China E-mail: [jgeng18@xjtu.edu.cn](jgeng18@xjtu.edu.cn) The ORCID identiﬁcation number(s) for the author(s) of this article can be found under [https://doi.org/10.1002/advs.202502395](https://doi.org/10.1002/advs.202502395)[ ](https://doi.org/10.1002/advs.202502395)© 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. DOI: 10.1002/advs.202502395 Y. Xin, X. Xiong, Y. Zhang, S. Zhang, S. Zhang, Y. Yang, R. Zhou, Z. Li, J. Geng National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy the Second Aﬃliated Hospital Xi’an Jiaotong University Xi’an 71000

FAQs

How do Calhm6-bearing ectosomes affect inflammatory responses?

Calhm6-bearing ectosomes suppress severe inflammation triggered by LPS by promoting an anti-inflammatory response and supporting immune tolerance.

What changes occur in macrophage polarization when Calhm6 is deficient?

Calhm6 deficiency suppresses Creb1 activity, leading to enhanced M1-like macrophage polarization with increased bactericidal activity and elevated pro-inflammatory cytokine secretion.

How does the Chp1-Camk4-Creb1 axis regulate polarization?

Chp1 acts as a scaffold and is phosphorylated by CaMK4, which enhances membrane localization of the Calhm6–Chp1–CaMK4 complex to activate Creb1 and drive M2-like polarization in a calcium-dependent manner.

Sep 29, 2026

Upload by Sarah