Interleukin-22 Protects Intestinal Stem Cells from Immune-Mediated Tissue Damage and Regulates Sensitivity to Graft versus Host Disease

Alan M. Hanash; Jarrod A. Dudakov; Guoqiang Hua; Margaret H. O'Connor; Lauren F. Young; Natalie V. Singer; Mallory L. West; Robert R. Jenq; Amanda M. Holland; Lucy W. Kappel; Arnab Ghosh; Jennifer J. Tsai; Uttam K. Rao; Nury L. Yim; Odette M. Smith; Enrico Velardi; Elena B. Hawryluk; George F. Murphy; Chen Liu; Lynette A. Fouser; Richard Kolesnick; Bruce R. Blazar; Marcel R M van den Brink

doi:10.1016/j.immuni.2012.05.028

Interleukin-22 Protects Intestinal Stem Cells from Immune-Mediated Tissue Damage and Regulates Sensitivity to Graft versus Host Disease

Alan M. Hanash, Jarrod A. Dudakov, Guoqiang Hua, Margaret H. O'Connor, Lauren F. Young, Natalie V. Singer, Mallory L. West, Robert R. Jenq, Amanda M. Holland, Lucy W. Kappel, Arnab Ghosh, Jennifer J. Tsai, Uttam K. Rao, Nury L. Yim, Odette M. Smith, Enrico Velardi, Elena B. Hawryluk, George F. Murphy, Chen Liu, Lynette A. FouserRichard Kolesnick, Bruce R. Blazar, Marcel R M van den Brink

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

482 Scopus citations

Abstract

Little is known about the maintenance of intestinal stem cells (ISCs) and progenitors during immune-mediated tissue damage or about the susceptibility of transplant recipients to tissue damage mediated by the donor immune system during graft versus host disease (GVHD). We demonstrate here that deficiency of recipient-derived IL-22 increased acute GVHD tissue damage and mortality, that ISCs were eliminated during GVHD, and that ISCs as well as their downstream progenitors expressed the IL-22 receptor. Intestinal IL-22 was produced after bone marrow transplant by IL-23-responsive innate lymphoid cells (ILCs) from the transplant recipients, and intestinal IL-22 increased in response to pretransplant conditioning. However, ILC frequency and IL-22 amounts were decreased by GVHD. Recipient IL-22 deficiency led to increased crypt apoptosis, depletion of ISCs, and loss of epithelial integrity. Our findings reveal IL-22 as a critical regulator of tissue sensitivity to GVHD and a protective factor for ISCs during inflammatory intestinal damage.

Original language	English (US)
Pages (from-to)	339-350
Number of pages	12
Journal	Immunity
Volume	37
Issue number	2
DOIs	https://doi.org/10.1016/j.immuni.2012.05.028
State	Published - Aug 24 2012

Bibliographical note

Funding Information:
Lgr5-LacZ mice were generously provided by H. Clevers. This research was supported by National Institutes of Health award numbers R01-HL069929 (M.v.d.B.), R01-CA107096 (M.R.M.v.d.B.), R01-AI080455 (M.R.M.v.d.B.), R01-AI 34495 (B.B.), R01-HL56067 (B.B.), and K08-KHL115355A (A.M. Hanash). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Support was also received from the American Society of Hematology Research Training Award for Fellows (A.M. Hanash), the American Society for Blood and Marrow Transplantation/Celgene New Investigator Award (A.M. Hanash), the AACR Judah Folkman Fellowship for Angiogenesis Research: 10-40-18-GHOS (A.G.), the US Department of Defense: USAMRAA Award W81XWH-09-1-0294 (M.R.M.v.d.B.), the Radiation Effects Research Foundation (RERF-NIAID) (M.R.M.v.d.B.), The Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center funded by Mr. William H. Goodwin and Mrs. Alice Goodwin, The Lymphoma Foundation, Alex’s Lemonade Stand, The Geoffrey Beene Cancer Research Center at Memorial Sloan-Kettering Cancer Center, and The Peter Solomon Fund. We appreciate the invaluable help of the Laboratory of Comparative Pathology and the Molecular Cytology Core Facility (supported by Cancer Center Support Grant NCI P30-CA008748) of Memorial Sloan-Kettering Cancer Center. L.F. had recent employment at Pfizer.

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Hanash, A. M., Dudakov, J. A., Hua, G., O'Connor, M. H., Young, L. F., Singer, N. V., West, M. L., Jenq, R. R., Holland, A. M., Kappel, L. W., Ghosh, A., Tsai, J. J., Rao, U. K., Yim, N. L., Smith, O. M., Velardi, E., Hawryluk, E. B., Murphy, G. F., Liu, C., ... van den Brink, M. R. M. (2012). Interleukin-22 Protects Intestinal Stem Cells from Immune-Mediated Tissue Damage and Regulates Sensitivity to Graft versus Host Disease. Immunity, 37(2), 339-350. https://doi.org/10.1016/j.immuni.2012.05.028

Hanash, AM, Dudakov, JA, Hua, G, O'Connor, MH, Young, LF, Singer, NV, West, ML, Jenq, RR, Holland, AM, Kappel, LW, Ghosh, A, Tsai, JJ, Rao, UK, Yim, NL, Smith, OM, Velardi, E, Hawryluk, EB, Murphy, GF, Liu, C, Fouser, LA, Kolesnick, R, Blazar, BR & van den Brink, MRM 2012, 'Interleukin-22 Protects Intestinal Stem Cells from Immune-Mediated Tissue Damage and Regulates Sensitivity to Graft versus Host Disease', Immunity, vol. 37, no. 2, pp. 339-350. https://doi.org/10.1016/j.immuni.2012.05.028

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title = "Interleukin-22 Protects Intestinal Stem Cells from Immune-Mediated Tissue Damage and Regulates Sensitivity to Graft versus Host Disease",

abstract = "Little is known about the maintenance of intestinal stem cells (ISCs) and progenitors during immune-mediated tissue damage or about the susceptibility of transplant recipients to tissue damage mediated by the donor immune system during graft versus host disease (GVHD). We demonstrate here that deficiency of recipient-derived IL-22 increased acute GVHD tissue damage and mortality, that ISCs were eliminated during GVHD, and that ISCs as well as their downstream progenitors expressed the IL-22 receptor. Intestinal IL-22 was produced after bone marrow transplant by IL-23-responsive innate lymphoid cells (ILCs) from the transplant recipients, and intestinal IL-22 increased in response to pretransplant conditioning. However, ILC frequency and IL-22 amounts were decreased by GVHD. Recipient IL-22 deficiency led to increased crypt apoptosis, depletion of ISCs, and loss of epithelial integrity. Our findings reveal IL-22 as a critical regulator of tissue sensitivity to GVHD and a protective factor for ISCs during inflammatory intestinal damage.",

author = "Hanash, {Alan M.} and Dudakov, {Jarrod A.} and Guoqiang Hua and O'Connor, {Margaret H.} and Young, {Lauren F.} and Singer, {Natalie V.} and West, {Mallory L.} and Jenq, {Robert R.} and Holland, {Amanda M.} and Kappel, {Lucy W.} and Arnab Ghosh and Tsai, {Jennifer J.} and Rao, {Uttam K.} and Yim, {Nury L.} and Smith, {Odette M.} and Enrico Velardi and Hawryluk, {Elena B.} and Murphy, {George F.} and Chen Liu and Fouser, {Lynette A.} and Richard Kolesnick and Blazar, {Bruce R.} and {van den Brink}, {Marcel R M}",

note = "Funding Information: Lgr5-LacZ mice were generously provided by H. Clevers. This research was supported by National Institutes of Health award numbers R01-HL069929 (M.v.d.B.), R01-CA107096 (M.R.M.v.d.B.), R01-AI080455 (M.R.M.v.d.B.), R01-AI 34495 (B.B.), R01-HL56067 (B.B.), and K08-KHL115355A (A.M. Hanash). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Support was also received from the American Society of Hematology Research Training Award for Fellows (A.M. Hanash), the American Society for Blood and Marrow Transplantation/Celgene New Investigator Award (A.M. Hanash), the AACR Judah Folkman Fellowship for Angiogenesis Research: 10-40-18-GHOS (A.G.), the US Department of Defense: USAMRAA Award W81XWH-09-1-0294 (M.R.M.v.d.B.), the Radiation Effects Research Foundation (RERF-NIAID) (M.R.M.v.d.B.), The Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center funded by Mr. William H. Goodwin and Mrs. Alice Goodwin, The Lymphoma Foundation, Alex{\textquoteright}s Lemonade Stand, The Geoffrey Beene Cancer Research Center at Memorial Sloan-Kettering Cancer Center, and The Peter Solomon Fund. We appreciate the invaluable help of the Laboratory of Comparative Pathology and the Molecular Cytology Core Facility (supported by Cancer Center Support Grant NCI P30-CA008748) of Memorial Sloan-Kettering Cancer Center. L.F. had recent employment at Pfizer. ",

year = "2012",

month = aug,

day = "24",

doi = "10.1016/j.immuni.2012.05.028",

language = "English (US)",

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T1 - Interleukin-22 Protects Intestinal Stem Cells from Immune-Mediated Tissue Damage and Regulates Sensitivity to Graft versus Host Disease

AU - Hanash, Alan M.

AU - Dudakov, Jarrod A.

AU - Hua, Guoqiang

AU - O'Connor, Margaret H.

AU - Young, Lauren F.

AU - Singer, Natalie V.

AU - West, Mallory L.

AU - Jenq, Robert R.

AU - Holland, Amanda M.

AU - Kappel, Lucy W.

AU - Ghosh, Arnab

AU - Tsai, Jennifer J.

AU - Rao, Uttam K.

AU - Yim, Nury L.

AU - Smith, Odette M.

AU - Velardi, Enrico

AU - Hawryluk, Elena B.

AU - Murphy, George F.

AU - Liu, Chen

AU - Fouser, Lynette A.

AU - Kolesnick, Richard

AU - Blazar, Bruce R.

AU - van den Brink, Marcel R M

N1 - Funding Information: Lgr5-LacZ mice were generously provided by H. Clevers. This research was supported by National Institutes of Health award numbers R01-HL069929 (M.v.d.B.), R01-CA107096 (M.R.M.v.d.B.), R01-AI080455 (M.R.M.v.d.B.), R01-AI 34495 (B.B.), R01-HL56067 (B.B.), and K08-KHL115355A (A.M. Hanash). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Support was also received from the American Society of Hematology Research Training Award for Fellows (A.M. Hanash), the American Society for Blood and Marrow Transplantation/Celgene New Investigator Award (A.M. Hanash), the AACR Judah Folkman Fellowship for Angiogenesis Research: 10-40-18-GHOS (A.G.), the US Department of Defense: USAMRAA Award W81XWH-09-1-0294 (M.R.M.v.d.B.), the Radiation Effects Research Foundation (RERF-NIAID) (M.R.M.v.d.B.), The Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center funded by Mr. William H. Goodwin and Mrs. Alice Goodwin, The Lymphoma Foundation, Alex’s Lemonade Stand, The Geoffrey Beene Cancer Research Center at Memorial Sloan-Kettering Cancer Center, and The Peter Solomon Fund. We appreciate the invaluable help of the Laboratory of Comparative Pathology and the Molecular Cytology Core Facility (supported by Cancer Center Support Grant NCI P30-CA008748) of Memorial Sloan-Kettering Cancer Center. L.F. had recent employment at Pfizer.

PY - 2012/8/24

Y1 - 2012/8/24

N2 - Little is known about the maintenance of intestinal stem cells (ISCs) and progenitors during immune-mediated tissue damage or about the susceptibility of transplant recipients to tissue damage mediated by the donor immune system during graft versus host disease (GVHD). We demonstrate here that deficiency of recipient-derived IL-22 increased acute GVHD tissue damage and mortality, that ISCs were eliminated during GVHD, and that ISCs as well as their downstream progenitors expressed the IL-22 receptor. Intestinal IL-22 was produced after bone marrow transplant by IL-23-responsive innate lymphoid cells (ILCs) from the transplant recipients, and intestinal IL-22 increased in response to pretransplant conditioning. However, ILC frequency and IL-22 amounts were decreased by GVHD. Recipient IL-22 deficiency led to increased crypt apoptosis, depletion of ISCs, and loss of epithelial integrity. Our findings reveal IL-22 as a critical regulator of tissue sensitivity to GVHD and a protective factor for ISCs during inflammatory intestinal damage.

AB - Little is known about the maintenance of intestinal stem cells (ISCs) and progenitors during immune-mediated tissue damage or about the susceptibility of transplant recipients to tissue damage mediated by the donor immune system during graft versus host disease (GVHD). We demonstrate here that deficiency of recipient-derived IL-22 increased acute GVHD tissue damage and mortality, that ISCs were eliminated during GVHD, and that ISCs as well as their downstream progenitors expressed the IL-22 receptor. Intestinal IL-22 was produced after bone marrow transplant by IL-23-responsive innate lymphoid cells (ILCs) from the transplant recipients, and intestinal IL-22 increased in response to pretransplant conditioning. However, ILC frequency and IL-22 amounts were decreased by GVHD. Recipient IL-22 deficiency led to increased crypt apoptosis, depletion of ISCs, and loss of epithelial integrity. Our findings reveal IL-22 as a critical regulator of tissue sensitivity to GVHD and a protective factor for ISCs during inflammatory intestinal damage.

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Interleukin-22 Protects Intestinal Stem Cells from Immune-Mediated Tissue Damage and Regulates Sensitivity to Graft versus Host Disease

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