A tissue injury sensing and repair pathway distinct from host pathogen defense

Siqi Liu; Yun Ha Hur; Xin Cai; Qian Cong; Yihao Yang; Chiwei Xu; Angelina M. Bilate; Kevin Andrew Uy Gonzales; S. Martina Parigi; Christopher J. Cowley; Brian Hurwitz; Ji Dung Luo; Tiffany Tseng; Shiri Gur-Cohen; Megan Sribour; Tatiana Omelchenko; John Levorse; Hilda Amalia Pasolli; Craig B. Thompson; Daniel Mucida; Elaine Fuchs

doi:10.1016/j.cell.2023.03.031

A tissue injury sensing and repair pathway distinct from host pathogen defense

Siqi Liu, Yun Ha Hur, Xin Cai, Qian Cong, Yihao Yang, Chiwei Xu, Angelina M. Bilate, Kevin Andrew Uy Gonzales, S. Martina Parigi, Christopher J. Cowley, Brian Hurwitz, Ji Dung Luo, Tiffany Tseng, Shiri Gur-Cohen, Megan Sribour, Tatiana Omelchenko, John Levorse, Hilda Amalia Pasolli, Craig B. Thompson, Daniel MucidaElaine Fuchs

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

10 Scopus citations

Abstract

Pathogen infection and tissue injury are universal insults that disrupt homeostasis. Innate immunity senses microbial infections and induces cytokines/chemokines to activate resistance mechanisms. Here, we show that, in contrast to most pathogen-induced cytokines, interleukin-24 (IL-24) is predominately induced by barrier epithelial progenitors after tissue injury and is independent of microbiome or adaptive immunity. Moreover, Il24 ablation in mice impedes not only epidermal proliferation and re-epithelialization but also capillary and fibroblast regeneration within the dermal wound bed. Conversely, ectopic IL-24 induction in the homeostatic epidermis triggers global epithelial-mesenchymal tissue repair responses. Mechanistically, Il24 expression depends upon both epithelial IL24-receptor/STAT3 signaling and hypoxia-stabilized HIF1α, which converge following injury to trigger autocrine and paracrine signaling involving IL-24-mediated receptor signaling and metabolic regulation. Thus, parallel to innate immune sensing of pathogens to resolve infections, epithelial stem cells sense injury signals to orchestrate IL-24-mediated tissue repair.

Original language	English (US)
Pages (from-to)	2127-2143.e22
Journal	Cell
Volume	186
Issue number	10
DOIs	https://doi.org/10.1016/j.cell.2023.03.031
State	Published - May 11 2023
Externally published	Yes

Keywords

STAT3
angiogenesis
coordinated tissue repair
epithelial stem cells
hypoxia
innate immune signaling
interferons
interleukin-24
microbiome-independent responses
tissue injury

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2023.03.031

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Liu, S., Hur, Y. H., Cai, X., Cong, Q., Yang, Y., Xu, C., Bilate, A. M., Gonzales, K. A. U., Parigi, S. M., Cowley, C. J., Hurwitz, B., Luo, J. D., Tseng, T., Gur-Cohen, S., Sribour, M., Omelchenko, T., Levorse, J., Pasolli, H. A., Thompson, C. B., ... Fuchs, E. (2023). A tissue injury sensing and repair pathway distinct from host pathogen defense. Cell, 186(10), 2127-2143.e22. https://doi.org/10.1016/j.cell.2023.03.031

Liu, S, Hur, YH, Cai, X , Cong, Q, Yang, Y, Xu, C, Bilate, AM, Gonzales, KAU, Parigi, SM, Cowley, CJ, Hurwitz, B, Luo, JD, Tseng, T, Gur-Cohen, S, Sribour, M, Omelchenko, T, Levorse, J, Pasolli, HA, Thompson, CB, Mucida, D & Fuchs, E 2023, 'A tissue injury sensing and repair pathway distinct from host pathogen defense', Cell, vol. 186, no. 10, pp. 2127-2143.e22. https://doi.org/10.1016/j.cell.2023.03.031

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title = "A tissue injury sensing and repair pathway distinct from host pathogen defense",

abstract = "Pathogen infection and tissue injury are universal insults that disrupt homeostasis. Innate immunity senses microbial infections and induces cytokines/chemokines to activate resistance mechanisms. Here, we show that, in contrast to most pathogen-induced cytokines, interleukin-24 (IL-24) is predominately induced by barrier epithelial progenitors after tissue injury and is independent of microbiome or adaptive immunity. Moreover, Il24 ablation in mice impedes not only epidermal proliferation and re-epithelialization but also capillary and fibroblast regeneration within the dermal wound bed. Conversely, ectopic IL-24 induction in the homeostatic epidermis triggers global epithelial-mesenchymal tissue repair responses. Mechanistically, Il24 expression depends upon both epithelial IL24-receptor/STAT3 signaling and hypoxia-stabilized HIF1α, which converge following injury to trigger autocrine and paracrine signaling involving IL-24-mediated receptor signaling and metabolic regulation. Thus, parallel to innate immune sensing of pathogens to resolve infections, epithelial stem cells sense injury signals to orchestrate IL-24-mediated tissue repair.",

keywords = "STAT3, angiogenesis, coordinated tissue repair, epithelial stem cells, hypoxia, innate immune signaling, interferons, interleukin-24, microbiome-independent responses, tissue injury",

author = "Siqi Liu and Hur, {Yun Ha} and Xin Cai and Qian Cong and Yihao Yang and Chiwei Xu and Bilate, {Angelina M.} and Gonzales, {Kevin Andrew Uy} and Parigi, {S. Martina} and Cowley, {Christopher J.} and Brian Hurwitz and Luo, {Ji Dung} and Tiffany Tseng and Shiri Gur-Cohen and Megan Sribour and Tatiana Omelchenko and John Levorse and Pasolli, {Hilda Amalia} and Thompson, {Craig B.} and Daniel Mucida and Elaine Fuchs",

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year = "2023",

month = may,

day = "11",

doi = "10.1016/j.cell.2023.03.031",

language = "English (US)",

volume = "186",

pages = "2127--2143.e22",

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T1 - A tissue injury sensing and repair pathway distinct from host pathogen defense

AU - Liu, Siqi

AU - Hur, Yun Ha

AU - Cai, Xin

AU - Cong, Qian

AU - Yang, Yihao

AU - Xu, Chiwei

AU - Bilate, Angelina M.

AU - Gonzales, Kevin Andrew Uy

AU - Parigi, S. Martina

AU - Cowley, Christopher J.

AU - Hurwitz, Brian

AU - Luo, Ji Dung

AU - Tseng, Tiffany

AU - Gur-Cohen, Shiri

AU - Sribour, Megan

AU - Omelchenko, Tatiana

AU - Levorse, John

AU - Pasolli, Hilda Amalia

AU - Thompson, Craig B.

AU - Mucida, Daniel

AU - Fuchs, Elaine

PY - 2023/5/11

Y1 - 2023/5/11

N2 - Pathogen infection and tissue injury are universal insults that disrupt homeostasis. Innate immunity senses microbial infections and induces cytokines/chemokines to activate resistance mechanisms. Here, we show that, in contrast to most pathogen-induced cytokines, interleukin-24 (IL-24) is predominately induced by barrier epithelial progenitors after tissue injury and is independent of microbiome or adaptive immunity. Moreover, Il24 ablation in mice impedes not only epidermal proliferation and re-epithelialization but also capillary and fibroblast regeneration within the dermal wound bed. Conversely, ectopic IL-24 induction in the homeostatic epidermis triggers global epithelial-mesenchymal tissue repair responses. Mechanistically, Il24 expression depends upon both epithelial IL24-receptor/STAT3 signaling and hypoxia-stabilized HIF1α, which converge following injury to trigger autocrine and paracrine signaling involving IL-24-mediated receptor signaling and metabolic regulation. Thus, parallel to innate immune sensing of pathogens to resolve infections, epithelial stem cells sense injury signals to orchestrate IL-24-mediated tissue repair.

AB - Pathogen infection and tissue injury are universal insults that disrupt homeostasis. Innate immunity senses microbial infections and induces cytokines/chemokines to activate resistance mechanisms. Here, we show that, in contrast to most pathogen-induced cytokines, interleukin-24 (IL-24) is predominately induced by barrier epithelial progenitors after tissue injury and is independent of microbiome or adaptive immunity. Moreover, Il24 ablation in mice impedes not only epidermal proliferation and re-epithelialization but also capillary and fibroblast regeneration within the dermal wound bed. Conversely, ectopic IL-24 induction in the homeostatic epidermis triggers global epithelial-mesenchymal tissue repair responses. Mechanistically, Il24 expression depends upon both epithelial IL24-receptor/STAT3 signaling and hypoxia-stabilized HIF1α, which converge following injury to trigger autocrine and paracrine signaling involving IL-24-mediated receptor signaling and metabolic regulation. Thus, parallel to innate immune sensing of pathogens to resolve infections, epithelial stem cells sense injury signals to orchestrate IL-24-mediated tissue repair.

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KW - angiogenesis

KW - coordinated tissue repair

KW - epithelial stem cells

KW - hypoxia

KW - innate immune signaling

KW - interferons

KW - interleukin-24

KW - microbiome-independent responses

KW - tissue injury

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A tissue injury sensing and repair pathway distinct from host pathogen defense

Abstract

Keywords

ASJC Scopus subject areas

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