Mechanosensation of cyclical force by PIEZO1 is essential for innate immunity

Angel G Solis; Piotr Bielecki; Holly R Steach; Lokesh Sharma; Christian C D Harman; Sanguk Yun; Marcel R de Zoete; James N Warnock; S D Filip To; Autumn G York; Matthias Mack; Martin A Schwartz; Charles S Dela Cruz; Noah W Palm; Ruaidhrí Jackson; Richard A Flavell

doi:10.1038/s41586-019-1485-8

Mechanosensation of cyclical force by PIEZO1 is essential for innate immunity

Angel G Solis, Piotr Bielecki, Holly R Steach, Lokesh Sharma, Christian C D Harman, Sanguk Yun, Marcel R de Zoete, James N Warnock, S D Filip To, Autumn G York, Matthias Mack, Martin A Schwartz, Charles S Dela Cruz, Noah W Palm, Ruaidhrí Jackson, Richard A Flavell

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Direct recognition of invading pathogens by innate immune cells is a critical driver of the inflammatory response. However, cells of the innate immune system can also sense their local microenvironment and respond to physiological fluctuations in temperature, pH, oxygen and nutrient availability, which are altered during inflammation. Although cells of the immune system experience force and pressure throughout their life cycle, little is known about how these mechanical processes regulate the immune response. Here we show that cyclical hydrostatic pressure, similar to that experienced by immune cells in the lung, initiates an inflammatory response via the mechanically activated ion channel PIEZO1. Mice lacking PIEZO1 in innate immune cells showed ablated pulmonary inflammation in the context of bacterial infection or fibrotic autoinflammation. Our results reveal an environmental sensory axis that stimulates innate immune cells to mount an inflammatory response, and demonstrate a physiological role for PIEZO1 and mechanosensation in immunity.

Original language	English
Pages (from-to)	69-74
Number of pages	6
Journal	Nature
Volume	573
Issue number	7772
DOIs	https://doi.org/10.1038/s41586-019-1485-8
Publication status	Published - 5 Sept 2019
Externally published	Yes

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Solis, A. G., Bielecki, P., Steach, H. R., Sharma, L., Harman, C. C. D., Yun, S., de Zoete, M. R., Warnock, J. N., To, S. D. F., York, A. G., Mack, M., Schwartz, M. A., Dela Cruz, C. S., Palm, N. W., Jackson, R., & Flavell, R. A. (2019). Mechanosensation of cyclical force by PIEZO1 is essential for innate immunity. Nature, 573(7772), 69-74. https://doi.org/10.1038/s41586-019-1485-8

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title = "Mechanosensation of cyclical force by PIEZO1 is essential for innate immunity",

abstract = "Direct recognition of invading pathogens by innate immune cells is a critical driver of the inflammatory response. However, cells of the innate immune system can also sense their local microenvironment and respond to physiological fluctuations in temperature, pH, oxygen and nutrient availability, which are altered during inflammation. Although cells of the immune system experience force and pressure throughout their life cycle, little is known about how these mechanical processes regulate the immune response. Here we show that cyclical hydrostatic pressure, similar to that experienced by immune cells in the lung, initiates an inflammatory response via the mechanically activated ion channel PIEZO1. Mice lacking PIEZO1 in innate immune cells showed ablated pulmonary inflammation in the context of bacterial infection or fibrotic autoinflammation. Our results reveal an environmental sensory axis that stimulates innate immune cells to mount an inflammatory response, and demonstrate a physiological role for PIEZO1 and mechanosensation in immunity.",

author = "Solis, {Angel G} and Piotr Bielecki and Steach, {Holly R} and Lokesh Sharma and Harman, {Christian C D} and Sanguk Yun and {de Zoete}, {Marcel R} and Warnock, {James N} and To, {S D Filip} and York, {Autumn G} and Matthias Mack and Schwartz, {Martin A} and {Dela Cruz}, {Charles S} and Palm, {Noah W} and Ruaidhr{\'i} Jackson and Flavell, {Richard A}",

note = "Funding Information: Acknowledgements We thank J. Alderman, C. Lieber, C. Hughes, E. H.-P. and P. Rainey for help in facilitating this work; B. Kazmierczak for providing the P. aeruginosa; M. Roulis for insightful comments and reagents; L. Orr for helpful insight regarding statistical analysis; I. Odell for help with computational software; C. Rothlin and Dr. C. Abraham for continued support and feedback as this work progressed; P.-M. Chen for help and reagents related to hypoxia studies. This work was supported by the Howard Hughes Medical Institute and the Blavatnik Family Foundation (R.A.F.). This work was supported in part by the Searle Scholars Program, the Leukemia Research Foundation, the Gruber Foundation and the NIH (R01GM122984). R.J. was supported in part by the Crohn{\textquoteright}s and Colitis Foundation. M.A.S. was supported by the NIH (HL RO1 75092). A.G.S. was supported in part by an NIH training grant (T32 GM007499) and the American Society for Microbiology. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

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doi = "10.1038/s41586-019-1485-8",

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AU - Bielecki, Piotr

AU - Steach, Holly R

AU - Sharma, Lokesh

AU - Harman, Christian C D

AU - Yun, Sanguk

AU - de Zoete, Marcel R

AU - Warnock, James N

AU - To, S D Filip

AU - York, Autumn G

AU - Mack, Matthias

AU - Schwartz, Martin A

AU - Dela Cruz, Charles S

AU - Palm, Noah W

AU - Jackson, Ruaidhrí

AU - Flavell, Richard A

N1 - Funding Information: Acknowledgements We thank J. Alderman, C. Lieber, C. Hughes, E. H.-P. and P. Rainey for help in facilitating this work; B. Kazmierczak for providing the P. aeruginosa; M. Roulis for insightful comments and reagents; L. Orr for helpful insight regarding statistical analysis; I. Odell for help with computational software; C. Rothlin and Dr. C. Abraham for continued support and feedback as this work progressed; P.-M. Chen for help and reagents related to hypoxia studies. This work was supported by the Howard Hughes Medical Institute and the Blavatnik Family Foundation (R.A.F.). This work was supported in part by the Searle Scholars Program, the Leukemia Research Foundation, the Gruber Foundation and the NIH (R01GM122984). R.J. was supported in part by the Crohn’s and Colitis Foundation. M.A.S. was supported by the NIH (HL RO1 75092). A.G.S. was supported in part by an NIH training grant (T32 GM007499) and the American Society for Microbiology. Publisher Copyright: © 2019, The Author(s), under exclusive licence to Springer Nature Limited. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

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N2 - Direct recognition of invading pathogens by innate immune cells is a critical driver of the inflammatory response. However, cells of the innate immune system can also sense their local microenvironment and respond to physiological fluctuations in temperature, pH, oxygen and nutrient availability, which are altered during inflammation. Although cells of the immune system experience force and pressure throughout their life cycle, little is known about how these mechanical processes regulate the immune response. Here we show that cyclical hydrostatic pressure, similar to that experienced by immune cells in the lung, initiates an inflammatory response via the mechanically activated ion channel PIEZO1. Mice lacking PIEZO1 in innate immune cells showed ablated pulmonary inflammation in the context of bacterial infection or fibrotic autoinflammation. Our results reveal an environmental sensory axis that stimulates innate immune cells to mount an inflammatory response, and demonstrate a physiological role for PIEZO1 and mechanosensation in immunity.

AB - Direct recognition of invading pathogens by innate immune cells is a critical driver of the inflammatory response. However, cells of the innate immune system can also sense their local microenvironment and respond to physiological fluctuations in temperature, pH, oxygen and nutrient availability, which are altered during inflammation. Although cells of the immune system experience force and pressure throughout their life cycle, little is known about how these mechanical processes regulate the immune response. Here we show that cyclical hydrostatic pressure, similar to that experienced by immune cells in the lung, initiates an inflammatory response via the mechanically activated ion channel PIEZO1. Mice lacking PIEZO1 in innate immune cells showed ablated pulmonary inflammation in the context of bacterial infection or fibrotic autoinflammation. Our results reveal an environmental sensory axis that stimulates innate immune cells to mount an inflammatory response, and demonstrate a physiological role for PIEZO1 and mechanosensation in immunity.

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Mechanosensation of cyclical force by PIEZO1 is essential for innate immunity

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