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Tuning immunity through tissue mechanotransduction

Nature Reviews Immunology volume 23, pages 174–188 (2023)Cite this article

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Abstract

Immune responses are governed by signals from the tissue microenvironment, and in addition to biochemical signals, mechanical cues and forces arising from the tissue, its extracellular matrix and its constituent cells shape immune cell function. Indeed, changes in biophysical properties of tissue alter the mechanical signals experienced by cells in many disease conditions, in inflammatory states and in the context of ageing. These mechanical cues are converted into biochemical signals through the process of mechanotransduction, and multiple pathways of mechanotransduction have been identified in immune cells. Such pathways impact important cellular functions including cell activation, cytokine production, metabolism, proliferation and trafficking. Changes in tissue mechanics may also represent a new form of ‘danger signal’ that alerts the innate and adaptive immune systems to the possibility of injury or infection. Tissue mechanics can change temporally during an infection or inflammatory response, offering a novel layer of dynamic immune regulation. Here, we review the emerging field of mechanoimmunology, focusing on how mechanical cues at the scale of the tissue environment regulate immune cell behaviours to initiate, propagate and resolve the immune response.

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Fig. 1: An overview of mechanotransduction pathways in cells.
Fig. 2: Mechanical regulation of T cell activity through YAP.
Fig. 3: Integration of mechanotransduction pathways and innate immune cell activation.
Fig. 4: Mechanical forces modulate acute immune responses.

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Acknowledgements

J.M.B. is a recipient of a National Institutes of Health (NIH) T32 (AG000266) postdoctoral fellowship award. This work was funded, in part, through the Huiying Memorial Foundation (D.A.W.), the Canadian Institutes of Health Research PJT169175 (D.A.W.), and the National Institutes of Health National Institute of Allergy and Infectious Diseases (NIAID) R01 AI151301 (W.F.L.), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) R21 AR077288 (W.F.L.) and the National Institute of Aging (NIA) R21 G069067 (W.F.L).

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Author notes

  1. These authors contributed equally: Huixun Du, Juliet M. Bartleson, Sergei Butenko, Valentina Alonso.

  2. These authors jointly supervised this work: Wendy F. Liu, Daniel A. Winer, Manish J. Butte.

Authors and Affiliations

  1. Buck Institute for Research on Aging, Novato, CA, USA

    Huixun Du, Juliet M. Bartleson & Daniel A. Winer

  2. Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA

    Huixun Du & Daniel A. Winer

  3. Department of Biomedical Engineering, University of California Irvine, Irvine, CA, USA

    Sergei Butenko & Wendy F. Liu

  4. Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA, USA

    Sergei Butenko & Wendy F. Liu

  5. UCI Edwards Sciences Foundation Cardiovascular Innovation and Research Center (CIRC), University of California Irvine, Irvine, CA, USA

    Sergei Butenko & Wendy F. Liu

  6. Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA

    Valentina Alonso & Manish J. Butte

  7. Department of Chemical and Biomolecular Engineering, University of California Irvine, Irvine, CA, USA

    Wendy F. Liu

  8. Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA

    Wendy F. Liu

  9. Institute for Immunology, University of California Irvine, Irvine, CA, USA

    Wendy F. Liu

  10. Division of Cellular & Molecular Biology, Toronto General Hospital Research Institute (TGHRI), University Health Network, Toronto, Ontario, Canada

    Daniel A. Winer

  11. Department of Immunology, University of Toronto, Toronto, Ontario, Canada

    Daniel A. Winer

  12. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

    Daniel A. Winer

  13. Department of Paediatrics, University of California Los Angeles, Los Angeles, CA, USA

    Manish J. Butte

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Supplementary information

Glossary

‘M1-like’ inflammatory macrophage

‘M1’ and ‘M2’ are classifications historically used to define macrophages activated in vitro as pro-inflammatory (when ‘classically’ activated with IFNγ and lipopolysaccharide (LPS)) or anti-inflammatory (when ‘alternatively’ activated with interleukin-4 (IL-4) or IL-10), respectively. However, in vivo macrophages are highly specialized, transcriptomically dynamic and extremely heterogeneous with regards to their phenotypes and functions, which are continuously shaped by their tissue microenvironment. Therefore, the M1 or M2 classification is too simplistic to explain the true nature of in vivo macrophages, although these terms are still often used to indicate whether the macrophages in question are more pro-inflammatory or anti-inflammatory.

Immunological synapse

The site of discrete contact formed between an antigen-presenting cell (APC) and a T cell. Similar synapses have been described in other immune cells such as natural killer cells or cytotoxic T cells, where the contact is formed with a target cell. It is important in establishing adhesion with the partner cell and polarization of the signalling and cytotoxic machinery. This structure is heavily influenced by the cytoskeleton and transduces controlled secretory signals, thereby allowing the directed release of cytokines or lytic granules towards the APC or target cell.

Annulus fibrosus

A ring of fibrous tissue, such as that surrounding an intervertebral disc or heart valve.

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Du, H., Bartleson, J.M., Butenko, S. et al. Tuning immunity through tissue mechanotransduction. Nat Rev Immunol 23, 174–188 (2023). https://doi.org/10.1038/s41577-022-00761-w

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