Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function

Dror S. Shouval; Amlan Biswas; Jeremy A. Goettel; Katelyn McCann; Evan Conaway; Naresh S. Redhu; Ivan D. Mascanfroni; Ziad AlAdham; Sydney Lavoie; Mouna Ibourk; Deanna D. Nguyen; Janneke N. Samsom; Johanna C. Escher; Raz Somech; Batia Weiss; Rita Beier; Laurie S. Conklin; Christen L. Ebens; Fernanda G.M.S. Santos; Alexandre R. Ferreira; Mary Sherlock; Atul K. Bhan; Werner Müller; J. Rodrigo Mora; Francisco J. Quintana; Christoph Klein; Aleixo M. Muise; Bruce H. Horwitz; Scott B. Snapper

doi:10.1016/j.immuni.2014.03.011

Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function

Dror S. Shouval, Amlan Biswas, Jeremy A. Goettel, Katelyn McCann, Evan Conaway, Naresh S. Redhu, Ivan D. Mascanfroni, Ziad AlAdham, Sydney Lavoie, Mouna Ibourk, Deanna D. Nguyen, Janneke N. Samsom, Johanna C. Escher, Raz Somech, Batia Weiss, Rita Beier, Laurie S. Conklin, Christen L. Ebens, Fernanda G.M.S. Santos, Alexandre R. FerreiraMary Sherlock, Atul K. Bhan, Werner Müller, J. Rodrigo Mora, Francisco J. Quintana, Christoph Klein, Aleixo M. Muise, Bruce H. Horwitz, Scott B. Snapper

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Abstract

Intact interleukin-10 receptor (IL-10R) signaling on effector and T regulatory (Treg) cells are each independently required to maintain immune tolerance. Here we show that IL-10 sensing by innate immune cells, independent of its effects on Tcells, was critical for regulating mucosal homeostasis. Following wild-type (WT) CD4⁺ Tcell transfer, Rag2^-/-Il10rb^-/- mice developed severe colitis in association with profound defects in generation and function of Treg cells. Moreover, loss of IL-10R signaling impaired the generation and function of anti-inflammatory intestinal and bone-marrow-derived macrophages and their ability to secrete IL-10. Importantly, transfer of WT but not Il10rb^-/- anti-inflammatory macrophages ameliorated colitis induction by WT CD4⁺ Tcells in Rag2^-/-Il10rb^-/- mice. Similar alterations in the generation and function of anti-inflammatory macrophages were observed in IL-10R-deficient patients with very early onset inflammatory bowel disease. Collectively, our studies define innate immune IL-10R signaling as a key factor regulating mucosal immune homeostasis in mice and humans.

Original language	English (US)
Pages (from-to)	706-719
Number of pages	14
Journal	Immunity
Volume	40
Issue number	5
DOIs	https://doi.org/10.1016/j.immuni.2014.03.011
State	Published - May 15 2014
Externally published	Yes

Bibliographical note

Funding Information:
D.S.S is a recipient of a Research Fellowship Award Grant from the Crohn’s and Colitis Foundation of America (RFA 3784). S.B.S is supported by NIH Grants HL59561, DK034854, and AI50950, the Helmsley Charitable Trust, and the Wolpow Family Chair in IBD Treatment and Research. We would like to thank Thaddeus Stappenbeck for providing us Il10rb −/− mice on the C57BL/6 background.

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Shouval, D. S., Biswas, A., Goettel, J. A., McCann, K., Conaway, E., Redhu, N. S., Mascanfroni, I. D., AlAdham, Z., Lavoie, S., Ibourk, M., Nguyen, D. D., Samsom, J. N., Escher, J. C., Somech, R., Weiss, B., Beier, R., Conklin, L. S., Ebens, C. L., Santos, F. G. M. S., ... Snapper, S. B. (2014). Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function. Immunity, 40(5), 706-719. https://doi.org/10.1016/j.immuni.2014.03.011

Shouval, DS, Biswas, A, Goettel, JA, McCann, K, Conaway, E, Redhu, NS, Mascanfroni, ID, AlAdham, Z, Lavoie, S, Ibourk, M, Nguyen, DD, Samsom, JN, Escher, JC, Somech, R, Weiss, B, Beier, R, Conklin, LS, Ebens, CL, Santos, FGMS, Ferreira, AR, Sherlock, M, Bhan, AK, Müller, W, Mora, JR, Quintana, FJ, Klein, C, Muise, AM, Horwitz, BH & Snapper, SB 2014, 'Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function', Immunity, vol. 40, no. 5, pp. 706-719. https://doi.org/10.1016/j.immuni.2014.03.011

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title = "Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function",

abstract = "Intact interleukin-10 receptor (IL-10R) signaling on effector and T regulatory (Treg) cells are each independently required to maintain immune tolerance. Here we show that IL-10 sensing by innate immune cells, independent of its effects on Tcells, was critical for regulating mucosal homeostasis. Following wild-type (WT) CD4+ Tcell transfer, Rag2-/-Il10rb-/- mice developed severe colitis in association with profound defects in generation and function of Treg cells. Moreover, loss of IL-10R signaling impaired the generation and function of anti-inflammatory intestinal and bone-marrow-derived macrophages and their ability to secrete IL-10. Importantly, transfer of WT but not Il10rb-/- anti-inflammatory macrophages ameliorated colitis induction by WT CD4+ Tcells in Rag2-/-Il10rb-/- mice. Similar alterations in the generation and function of anti-inflammatory macrophages were observed in IL-10R-deficient patients with very early onset inflammatory bowel disease. Collectively, our studies define innate immune IL-10R signaling as a key factor regulating mucosal immune homeostasis in mice and humans.",

author = "Shouval, {Dror S.} and Amlan Biswas and Goettel, {Jeremy A.} and Katelyn McCann and Evan Conaway and Redhu, {Naresh S.} and Mascanfroni, {Ivan D.} and Ziad AlAdham and Sydney Lavoie and Mouna Ibourk and Nguyen, {Deanna D.} and Samsom, {Janneke N.} and Escher, {Johanna C.} and Raz Somech and Batia Weiss and Rita Beier and Conklin, {Laurie S.} and Ebens, {Christen L.} and Santos, {Fernanda G.M.S.} and Ferreira, {Alexandre R.} and Mary Sherlock and Bhan, {Atul K.} and Werner M{\"u}ller and Mora, {J. Rodrigo} and Quintana, {Francisco J.} and Christoph Klein and Muise, {Aleixo M.} and Horwitz, {Bruce H.} and Snapper, {Scott B.}",

note = "Funding Information: D.S.S is a recipient of a Research Fellowship Award Grant from the Crohn{\textquoteright}s and Colitis Foundation of America (RFA 3784). S.B.S is supported by NIH Grants HL59561, DK034854, and AI50950, the Helmsley Charitable Trust, and the Wolpow Family Chair in IBD Treatment and Research. We would like to thank Thaddeus Stappenbeck for providing us Il10rb −/− mice on the C57BL/6 background. ",

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AU - Shouval, Dror S.

AU - Biswas, Amlan

AU - Goettel, Jeremy A.

AU - McCann, Katelyn

AU - Conaway, Evan

AU - Redhu, Naresh S.

AU - Mascanfroni, Ivan D.

AU - AlAdham, Ziad

AU - Lavoie, Sydney

AU - Ibourk, Mouna

AU - Nguyen, Deanna D.

AU - Samsom, Janneke N.

AU - Escher, Johanna C.

AU - Somech, Raz

AU - Weiss, Batia

AU - Beier, Rita

AU - Conklin, Laurie S.

AU - Ebens, Christen L.

AU - Santos, Fernanda G.M.S.

AU - Ferreira, Alexandre R.

AU - Sherlock, Mary

AU - Bhan, Atul K.

AU - Müller, Werner

AU - Mora, J. Rodrigo

AU - Quintana, Francisco J.

AU - Klein, Christoph

AU - Muise, Aleixo M.

AU - Horwitz, Bruce H.

AU - Snapper, Scott B.

N1 - Funding Information: D.S.S is a recipient of a Research Fellowship Award Grant from the Crohn’s and Colitis Foundation of America (RFA 3784). S.B.S is supported by NIH Grants HL59561, DK034854, and AI50950, the Helmsley Charitable Trust, and the Wolpow Family Chair in IBD Treatment and Research. We would like to thank Thaddeus Stappenbeck for providing us Il10rb −/− mice on the C57BL/6 background.

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N2 - Intact interleukin-10 receptor (IL-10R) signaling on effector and T regulatory (Treg) cells are each independently required to maintain immune tolerance. Here we show that IL-10 sensing by innate immune cells, independent of its effects on Tcells, was critical for regulating mucosal homeostasis. Following wild-type (WT) CD4+ Tcell transfer, Rag2-/-Il10rb-/- mice developed severe colitis in association with profound defects in generation and function of Treg cells. Moreover, loss of IL-10R signaling impaired the generation and function of anti-inflammatory intestinal and bone-marrow-derived macrophages and their ability to secrete IL-10. Importantly, transfer of WT but not Il10rb-/- anti-inflammatory macrophages ameliorated colitis induction by WT CD4+ Tcells in Rag2-/-Il10rb-/- mice. Similar alterations in the generation and function of anti-inflammatory macrophages were observed in IL-10R-deficient patients with very early onset inflammatory bowel disease. Collectively, our studies define innate immune IL-10R signaling as a key factor regulating mucosal immune homeostasis in mice and humans.

AB - Intact interleukin-10 receptor (IL-10R) signaling on effector and T regulatory (Treg) cells are each independently required to maintain immune tolerance. Here we show that IL-10 sensing by innate immune cells, independent of its effects on Tcells, was critical for regulating mucosal homeostasis. Following wild-type (WT) CD4+ Tcell transfer, Rag2-/-Il10rb-/- mice developed severe colitis in association with profound defects in generation and function of Treg cells. Moreover, loss of IL-10R signaling impaired the generation and function of anti-inflammatory intestinal and bone-marrow-derived macrophages and their ability to secrete IL-10. Importantly, transfer of WT but not Il10rb-/- anti-inflammatory macrophages ameliorated colitis induction by WT CD4+ Tcells in Rag2-/-Il10rb-/- mice. Similar alterations in the generation and function of anti-inflammatory macrophages were observed in IL-10R-deficient patients with very early onset inflammatory bowel disease. Collectively, our studies define innate immune IL-10R signaling as a key factor regulating mucosal immune homeostasis in mice and humans.

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Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function

Abstract

Bibliographical note

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