Lymphotoxin beta receptor signaling limits mucosal damage through driving IL-23 production by epithelial cells

E. Macho-Fernandez; E. P. Koroleva; C. M. Spencer; M. Tighe; E. Torrado; A. M. Cooper; Y. X. Fu; A. V. Tumanov

doi:10.1038/mi.2014.78

Lymphotoxin beta receptor signaling limits mucosal damage through driving IL-23 production by epithelial cells

E. Macho-Fernandez, E. P. Koroleva, C. M. Spencer, M. Tighe, E. Torrado, A. M. Cooper, Y. X. Fu, A. V. Tumanov

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

54 Scopus citations

Abstract

The immune mechanisms regulating epithelial cell repair after injury remain poorly defined. We demonstrate here that lymphotoxin beta receptor (LTβR) signaling in intestinal epithelial cells promotes self-repair after mucosal damage. Using a conditional gene-targeted approach, we demonstrate that LTβR signaling in intestinal epithelial cells is essential for epithelial interleukin-23 (IL-23) production and protection against epithelial injury. We further show that epithelial-derived IL-23 promotes mucosal wound healing by inducing the IL-22-mediated proliferation and survival of epithelial cells and mucus production. Additionally, we identified CD4 - CCR6 + T-bet - RAR-related orphan receptor gamma t (RORγt) + lymphoid tissue inducer cells as the main producers of protective IL-22 after epithelial damage. Thus, our results reveal a novel role for LTβR signaling in epithelial cells in the regulation of intestinal epithelial cell homeostasis to limit mucosal damage.

Original language	English (US)
Pages (from-to)	403-413
Number of pages	11
Journal	Mucosal Immunology
Volume	8
Issue number	2
DOIs	https://doi.org/10.1038/mi.2014.78
State	Published - Mar 14 2015

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1038/mi.2014.78

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@article{29a48744fca14073add65e56649cadde,

title = "Lymphotoxin beta receptor signaling limits mucosal damage through driving IL-23 production by epithelial cells",

abstract = "The immune mechanisms regulating epithelial cell repair after injury remain poorly defined. We demonstrate here that lymphotoxin beta receptor (LTβR) signaling in intestinal epithelial cells promotes self-repair after mucosal damage. Using a conditional gene-targeted approach, we demonstrate that LTβR signaling in intestinal epithelial cells is essential for epithelial interleukin-23 (IL-23) production and protection against epithelial injury. We further show that epithelial-derived IL-23 promotes mucosal wound healing by inducing the IL-22-mediated proliferation and survival of epithelial cells and mucus production. Additionally, we identified CD4 - CCR6 + T-bet - RAR-related orphan receptor gamma t (RORγt) + lymphoid tissue inducer cells as the main producers of protective IL-22 after epithelial damage. Thus, our results reveal a novel role for LTβR signaling in epithelial cells in the regulation of intestinal epithelial cell homeostasis to limit mucosal damage.",

author = "E. Macho-Fernandez and Koroleva, {E. P.} and Spencer, {C. M.} and M. Tighe and E. Torrado and Cooper, {A. M.} and Fu, {Y. X.} and Tumanov, {A. V.}",

note = "Funding Information: This work was supported by the National Institutes of Health (CA141975 to Y.-X.F.), Crohn{\textquoteright}s and Colitis Foundation of America (Senior Research Award #294083) to A.V.T., and by Trudeau Institute. We are grateful to N. Ghilardi and W. Ouyang (Genentech, CA) for providing IL-23-GFP+/− mice and IL-22-expressing plasmid, M. Holzenberger (INSERM, France) for providing MeuCre40 mice. We thank J. Browning and M. Ols (Biogen Idec) for providing reagents.",

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doi = "10.1038/mi.2014.78",

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AU - Macho-Fernandez, E.

AU - Koroleva, E. P.

AU - Spencer, C. M.

AU - Tighe, M.

AU - Torrado, E.

AU - Cooper, A. M.

AU - Fu, Y. X.

AU - Tumanov, A. V.

N1 - Funding Information: This work was supported by the National Institutes of Health (CA141975 to Y.-X.F.), Crohn’s and Colitis Foundation of America (Senior Research Award #294083) to A.V.T., and by Trudeau Institute. We are grateful to N. Ghilardi and W. Ouyang (Genentech, CA) for providing IL-23-GFP+/− mice and IL-22-expressing plasmid, M. Holzenberger (INSERM, France) for providing MeuCre40 mice. We thank J. Browning and M. Ols (Biogen Idec) for providing reagents.

PY - 2015/3/14

Y1 - 2015/3/14

N2 - The immune mechanisms regulating epithelial cell repair after injury remain poorly defined. We demonstrate here that lymphotoxin beta receptor (LTβR) signaling in intestinal epithelial cells promotes self-repair after mucosal damage. Using a conditional gene-targeted approach, we demonstrate that LTβR signaling in intestinal epithelial cells is essential for epithelial interleukin-23 (IL-23) production and protection against epithelial injury. We further show that epithelial-derived IL-23 promotes mucosal wound healing by inducing the IL-22-mediated proliferation and survival of epithelial cells and mucus production. Additionally, we identified CD4 - CCR6 + T-bet - RAR-related orphan receptor gamma t (RORγt) + lymphoid tissue inducer cells as the main producers of protective IL-22 after epithelial damage. Thus, our results reveal a novel role for LTβR signaling in epithelial cells in the regulation of intestinal epithelial cell homeostasis to limit mucosal damage.

AB - The immune mechanisms regulating epithelial cell repair after injury remain poorly defined. We demonstrate here that lymphotoxin beta receptor (LTβR) signaling in intestinal epithelial cells promotes self-repair after mucosal damage. Using a conditional gene-targeted approach, we demonstrate that LTβR signaling in intestinal epithelial cells is essential for epithelial interleukin-23 (IL-23) production and protection against epithelial injury. We further show that epithelial-derived IL-23 promotes mucosal wound healing by inducing the IL-22-mediated proliferation and survival of epithelial cells and mucus production. Additionally, we identified CD4 - CCR6 + T-bet - RAR-related orphan receptor gamma t (RORγt) + lymphoid tissue inducer cells as the main producers of protective IL-22 after epithelial damage. Thus, our results reveal a novel role for LTβR signaling in epithelial cells in the regulation of intestinal epithelial cell homeostasis to limit mucosal damage.

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Lymphotoxin beta receptor signaling limits mucosal damage through driving IL-23 production by epithelial cells

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