Matrix Stiffness Regulates Interleukin-10 Secretion in Human Microglia (HMC3) via YAP-Mediated Mechanotransduction

Xue Fang; Haiying Jia; Shaoshan Pan; Qian Liu; Qian Wang; Ye Feng; Weiping Ding; Tianzhi Luo

doi:10.1002/cbf.70061

Matrix Stiffness Regulates Interleukin-10 Secretion in Human Microglia (HMC3) via YAP-Mediated Mechanotransduction

Cell Biochem Funct. 2025 Mar;43(3):e70061. doi: 10.1002/cbf.70061.

Authors

Xue Fang¹, Haiying Jia², Shaoshan Pan¹, Qian Liu¹, Qian Wang¹, Ye Feng¹, Weiping Ding³, Tianzhi Luo^{1

4}

Affiliations

¹ CAS Key Laboratory of Mechanical Behavior and Design of Materials, Department of Modern Mechanics, University of Science and Technology of China, Hefei, China.
² Chinese People's Liberation Army Strategic Support Force Special Medical Center, Beijing, China.
³ School of Information Science and Technology, University of Science and Technology of China, Hefei, China.
⁴ The First Affiliated Hospital, University of Science and Technology of China, Hefei, China.

PMID: 40011226
DOI: 10.1002/cbf.70061

Abstract

Microglia, as resident immune cells in the brain, adhere to the extracellular matrix and typically exhibit anti-inflammatory polarization under normal physiological conditions. Despite their pivotal roles, the regulatory effects of extracellular matrix properties on microglial function and the associated molecular mechanisms remain inadequately understood. Here, we elucidate how matrix stiffness modulates interleukin-10 (IL-10) secretion in human microglia (HMC3) via yes-associated protein (YAP)-mediated mechanotransduction. Using soft collagen Ⅰ-coated hydrogels, we observed a substantial reduction in IL-10 secretion, accompanied by a decrease in the expression and nuclear localization of YAP compared to cells adhered to glass substrates. With increasing hydrogel substrate stiffness, the expression and nuclear localization of YAP were enhanced, leading to an elevated secretion of IL-10. Subsequently, to further investigate the relationship between YAP and IL-10, we performed YAP depletion experiments, which revealed that nuclear exclusion of YAP suppressed IL-10 secretion. Interestingly, overexpression of YAP in microglia did not markedly affect IL-10 levels. We seeded YAP-knockdown microglia onto hydrogels of varying stiffness, and no significant differences were observed in IL-10 secretion. Our findings suggested that cytoskeletal polymerization was crucial for the regulation of IL-10 secretion mediated by YAP. Given the crucial role of IL-10 in the tumor microenvironment, we further found shYAP-microglia attenuated the pro-proliferative effect of microglia on gliomas. Besides, when YAP was silenced, actin of human microglia decreased, and their contractility was weakened. In summary, this study identifies YAP as a pivotal molecule in controlling cytokine secretion and sensing matrix stiffness in microglia. These insights offer potential therapeutic avenues for glioma treatment by targeting YAP-mediated pathways in microglial cells.

Keywords: HMC3; glioma proliferation; human microglia; interleukin‐10; matrix stiffness; yes‐associated protein.

MeSH terms

Adaptor Proteins, Signal Transducing* / genetics
Adaptor Proteins, Signal Transducing* / metabolism
Cells, Cultured
Extracellular Matrix* / metabolism
Humans
Hydrogels / chemistry
Interleukin-10* / metabolism
Mechanotransduction, Cellular*
Microglia* / cytology
Microglia* / metabolism
Transcription Factors* / metabolism
YAP-Signaling Proteins

Substances

Interleukin-10
YAP-Signaling Proteins
YAP1 protein, human
Adaptor Proteins, Signal Transducing
Transcription Factors
IL10 protein, human
Hydrogels

Grants and funding

The work was supported by the National Science Foundation of China (82072018), Anhui Provincial Natural Science Foundation (2208085QH256), The Fundamental Research Funds for Central Universities (WK2480000006, WK9100000001), The Key Research and Development Project of Anhui Province (2022e07020012).