Mechanical Stiffness Controls Dendritic Cell Metabolism and Function

• Published in: Cell reports (Cambridge) Vol. 34; no. 2; p. 108609
• Main Authors: Chakraborty, Mainak, Chu, Kevin, Shrestha, Annie, Revelo, Xavier S., Zhang, Xiangyue, Gold, Matthew J., Khan, Saad, Lee, Megan, Huang, Camille, Akbari, Masoud, Barrow, Fanta, Chan, Yi Tao, Lei, Helena, Kotoulas, Nicholas K., Jovel, Juan, Pastrello, Chiara, Kotlyar, Max, Goh, Cynthia, Michelakis, Evangelos, Clemente-Casares, Xavier, Ohashi, Pamela S., Engleman, Edgar G., Winer, Shawn, Jurisica, Igor, Tsai, Sue, Winer, Daniel A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.01.2021; Elsevier
• Subjects: danger signals; dendritic cells; Dendritic Cells - immunology; Humans; Immunity, Innate - immunology; immunometabolism; Immunotherapy - methods; inflammation; innate immunity; mechanoimmunology; mechanosensing; PIEZO1; Signal Transduction; TAZ; tension; Vascular Stiffness - immunology; mechanoimmunology; mechanosensing; tension; dendritic cells; innate immunity; immunometabolism; inflammation; PIEZO1; danger signals; TAZ
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108609

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. [Display omitted] •Environmental stiffness promotes DC inflammatory function•Tension primes DC metabolism, even without pattern recognition receptor input•TAZ bridges mechanosensory signals to DC metabolism and function•Tension directs phenotypes of human monocyte-derived DCs The immune system is carefully tuned to respond to dangers in the environment. Chakraborty et al. show that environmental stiffness controls dendritic cell metabolism, phenotype, and inflammatory function through downstream Hippo-signaling mediators. The findings provide evidence for mechanical force as an integral node directing innate immune responses.