Mechanical Stiffness Controls Dendritic Cell Metabolism and Function

• DOI: 10.1016/j.celrep.2020.108609
• Publication Date: 2021-01-14T06:07:51Z
• Authors: Mainak Chakraborty; Kevin Chu; Annie Shrestha; Xavier S. Revelo; Xiangyue Zhang; Matthew J. Gold; Saad Khan; Megan Lee; Camille Huang; Masoud Akbari; Fanta Barrow; Yi Tao Chan; Helena Lei; Nicholas K. Kotoulas; Juan Jovel; Chiara Pastrello; Max Kotlyar; Cynthia Goh; Evangelos Michelakis; Xavier Clemente-C...; Pamela S. Ohashi; Edgar G. Engleman; Shawn Winer; Igor Jurisica; Sue Tsai; Daniel A. Winer
• Keywords: 0301 basic medicine; QH301-705.5; immunometabolism; Dendritic Cells; tension; Immunity, Innate; 3. Good health; 03 medical and health sciences; Vascular Stiffness; danger signals; Humans; mechanosensing; dendritic cells; Immunotherapy; Biology (General); innate immunity; Signal Transduction

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.