期刊
CELL REPORTS
卷 34, 期 2, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2020.108609
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资金
- Queen Elizabeth II Graduate Scholarship in Science and Technology (QEII-GSST)/Aventis Pasteur
- Banting and Best Diabetes Centre (BBDC)-Novo Nordisk Studentship
- National Research Council
- Tier 2 Canada Research Chair in Immunometabolism and Diabetes
- Li Ka Shing Institute of Virology Bridge Fund
- New Frontiers in Research-Exploration Fund
- Canadian Institutes of Health Research (CIHR) New Investigator Foundation Grant [FDN-148385]
- Huiying Memorial Foundation
- Ontario Ministry of Innovation Early Researcher Award
- Ontario Research Fund [34876]
- Natural Sciences Research Council (NSERC) [203475]
- Canada Foundation for Innovation (CFI) [29272, 225404, 33536]
- Buchan Foundation
- IBM
This study reveals that static tension impacts immune cell function, maturation, and metabolism, with cells grown at physiological resting stiffness showing reduced proliferation, activation, and cytokine production compared to cells grown under higher stiffness. The findings suggest that mechanical stiffness is a critical environmental cue affecting dendritic cells and innate immunity.
Stiffness in the tissue microenvironment changes in most diseases and immunological conditions, but its direct influence on the immune system is poorly understood. Here, we show that static tension impacts immune cell function, maturation, and metabolism. Bone-marrow-derived and/or splenic dendritic cells (DCs) grown in vitro at physiological resting stiffness have reduced proliferation, activation, and cytokine production compared with cells grown under higher stiffness, mimicking fibro-inflammatory disease. Consistently, DCs grown under higher stiffness show increased activation and flux of major glucose metabolic pathways. In DC models of autoimmune diabetes and tumor immunotherapy, tension primes DCs to elicit an adaptive immune response. Mechanistic workup identifies the Hippo-signaling molecule, TAZ, as well as Ca2+-related ion channels, including potentially PIEZO1, as important effectors impacting DC metabolism and function under tension. Tension also directs the phenotypes of monocyte-derived DCs in humans. Thus, mechanical stiffness is a critical environmental cue of DCs and innate immunity.
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