Mechanical Stiffness Controls Dendritic Cell Metabolism and Function

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-Casares; Pamela S Ohashi; Edgar G Engleman; Shawn Winer; Igor Jurisica; Sue Tsai; Daniel A Winer

doi:10.1016/j.celrep.2020.108609

Mechanical Stiffness Controls Dendritic Cell Metabolism and Function

Cell Rep. 2021 Jan 12;34(2):108609. doi: 10.1016/j.celrep.2020.108609.

Authors

Mainak Chakraborty¹, Kevin Chu², Annie Shrestha³, Xavier S Revelo⁴, Xiangyue Zhang⁵, Matthew J Gold⁶, Saad Khan⁷, Megan Lee², Camille Huang², Masoud Akbari², Fanta Barrow⁸, Yi Tao Chan⁹, Helena Lei¹, Nicholas K Kotoulas¹⁰, Juan Jovel¹¹, Chiara Pastrello¹², Max Kotlyar¹², Cynthia Goh¹⁰, Evangelos Michelakis¹³, Xavier Clemente-Casares², Pamela S Ohashi¹⁴, Edgar G Engleman⁵, Shawn Winer¹⁵, Igor Jurisica¹⁶, Sue Tsai¹⁷, Daniel A Winer¹⁸

Affiliations

¹ Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Hospital Research Institute (TGHRI), University Health Network, Toronto, ON M5G 1L7, Canada.
² Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada.
³ Faculty of Dentistry, University of Toronto, Toronto, ON M5G 1G6, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁴ Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA.
⁵ School of Medicine, Department of Pathology, Stanford University, Palo Alto, CA, USA.
⁶ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
⁷ Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Hospital Research Institute (TGHRI), University Health Network, Toronto, ON M5G 1L7, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁸ Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA.
⁹ Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
¹⁰ Department of Chemistry, University of Toronto, Toronto, ON, Canada.
¹¹ The Applied Genomics Core, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2E1, Canada.
¹² Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, and Data Science Discovery Centre for Chronic Diseases, Krembil Research Institute, Toronto, ON M5T 0S8, Canada.
¹³ Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada.
¹⁴ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
¹⁵ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Laboratory Medicine, St. Michael's Hospital, Toronto, ON M5B 1W8, Canada.
¹⁶ Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, and Data Science Discovery Centre for Chronic Diseases, Krembil Research Institute, Toronto, ON M5T 0S8, Canada; Departments of Medical Biophysics and Computer Science, University of Toronto, Toronto, ON, Canada; Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia.
¹⁷ Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada. Electronic address: stsai@ualberta.ca.
¹⁸ Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Hospital Research Institute (TGHRI), University Health Network, Toronto, ON M5G 1L7, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Pathology, University Health Network, Toronto, ON M5G 2C4, Canada; Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA. Electronic address: dwiner@buckinstitute.org.

PMID: 33440149
DOI: 10.1016/j.celrep.2020.108609

Abstract

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.

Keywords: PIEZO1; TAZ; danger signals; dendritic cells; immunometabolism; inflammation; innate immunity; mechanoimmunology; mechanosensing; tension.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dendritic Cells / immunology*
Humans
Immunity, Innate / immunology*
Immunotherapy / methods*
Signal Transduction
Vascular Stiffness / immunology*

Grants and funding

FDN-148385/CIHR/Canada