2. Academic Validation
  3. Calhm6 Governs Macrophage Polarization Through Chp1-Camk4-Creb1 Axis and Ectosomal Delivery in Inflammatory Responses

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

  • Adv Sci (Weinh). 2025 Sep 26:e02395. doi: 10.1002/advs.202502395.
Yanlong Xin 1 2 3 4,  Xiaofan Xiong 1 2 3 4,  Yan Zhang 2 3 4,  Siyu Zhang 2 3 4,  Shuting Zhang 2 3 4,  Yu Yang 2 3 4,  Yingxue Liang 3 4,  Lulu Zang 3 4,  Xi Chen 3 4,  Wenjuan Li 3 4,  Issam Halalmeh 3 4,  Rui Zhou 1 2 5 6 7,  Zongfang Li 1 2 5 6 7,  Haowen Liu 8,  Jing Geng 1 2 3 5 6 7
Affiliations

Affiliations

  • 1 Department of General Surgery, the Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, China.
  • 2 National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, the Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, China.
  • 3 International Joint Research Center on Cell Stress and Disease Diagnosis and Therapy, the Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, China.
  • 4 Precision Medicine Institute, the Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, China.
  • 5 Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, the Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, China.
  • 6 Shaanxi International Cooperation Base for Inflammation and Immunity, the Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, China.
  • 7 Shaanxi Provincial Academician Workstation, the Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, China.
  • 8 School of Life Sciences and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.
PMID: 40999918 DOI: 10.1002/advs.202502395
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.

Keywords

Calhm6; ectosomes; inflammatory response; ion channel; macrophage polarization.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z