Cell Reports (Jan 2021)
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
Affiliations
- Mainak Chakraborty
- Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Hospital Research Institute (TGHRI), University Health Network, Toronto, ON M5G 1L7, Canada
- Kevin Chu
- Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada
- Annie Shrestha
- 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
- Xavier S. Revelo
- Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA
- Xiangyue Zhang
- School of Medicine, Department of Pathology, Stanford University, Palo Alto, CA, USA
- Matthew J. Gold
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada
- Saad Khan
- 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
- Megan Lee
- Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada
- Camille Huang
- Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada
- Masoud Akbari
- Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada
- Fanta Barrow
- Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA
- Yi Tao Chan
- Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Helena Lei
- Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Hospital Research Institute (TGHRI), University Health Network, Toronto, ON M5G 1L7, Canada
- Nicholas K. Kotoulas
- Department of Chemistry, University of Toronto, Toronto, ON, Canada
- Juan Jovel
- The Applied Genomics Core, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2E1, Canada
- Chiara Pastrello
- 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
- Max Kotlyar
- 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
- Cynthia Goh
- Department of Chemistry, University of Toronto, Toronto, ON, Canada
- Evangelos Michelakis
- Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada
- Xavier Clemente-Casares
- Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada
- Pamela S. Ohashi
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Edgar G. Engleman
- School of Medicine, Department of Pathology, Stanford University, Palo Alto, CA, USA
- Shawn Winer
- 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
- Igor Jurisica
- 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
- Sue Tsai
- Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada; Corresponding author
- Daniel A. Winer
- 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; Corresponding author
- Journal volume & issue
-
Vol. 34,
no. 2
p. 108609
Abstract
Summary: 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.
