Interleukin-10 Receptor Signaling in Innate Immune Cells Regulates Mucosal Immune Tolerance and Anti-Inflammatory Macrophage Function

被引：465

作者：

Shouval, Dror S. ^{[1
,2
]}

Biswas, Amlan ^{[1
,2
]}

Goettel, Jeremy A. ^{[1
,2
]}

McCann, Katelyn ^{[1
,2
]}

Conaway, Evan ^{[3
]}

Redhu, Naresh S. ^{[1
,2
]}

Mascanfroni, Ivan D. ^{[4
]}

Al Adham, Ziad ^{[5
]}

Lavoie, Sydney ^{[1
]}

Ibourk, Mouna ^{[1
]}

Nguyen, Deanna D. ^{[6
,7
]}

Samsom, Janneke N. ^{[8
]}

Escher, Johanna C. ^{[9
]}

Somech, Raz ^{[10
,12
]}

Weiss, Batia ^{[11
,12
]}

Beier, Rita ^{[13
]}

Conklin, Laurie S. ^{[14
]}

Ebens, Christen L. ^{[15
]}

Santos, Fernanda G. M. S. ^{[16
]}

Ferreira, Alexandre R. ^{[16
]}

Sherlock, Mary ^{[17
]}

Bhan, Atul K. ^{[18
,19
]}

Mueller, Werner ^{[20
]}

Mora, J. Rodrigo ^{[6
,7
]}

Quintana, Francisco J. ^{[4
]}

Klein, Christoph ^{[21
]}

Muise, Aleixo M. ^{[5
]}

Horwitz, Bruce H. ^{[2
,3
]}

Snapper, Scott B. ^{[1
,7
,22
]}

机构：

[1] Boston Childrens Hosp, Div Gastroenterol Hepatol & Nutr, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA

[3] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[4] Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA

[5] Hosp Sick Children, Dept Paediat, Div Gastroenterol Hepatol & Nutr, Toronto, ON M5G 1X8, Canada

[6] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA

[7] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

[8] Sophia Childrens Univ Hosp, Lab Pediat Gastroenterol, Erasmus Med Ctr, NL-3000 CA Rotterdam, Netherlands

[9] Sophia Childrens Univ Hosp, Dept Pediat, Erasmus Med Ctr, NL-3000 CA Rotterdam, Netherlands

[10] Edmond & Lily Safra Childrens Hosp, Sheba Med Ctr, Pediat Immunol Serv, IL-52661 Tel Hashomer, Israel

[11] Edmond & Lily Safra Childrens Hosp, Sheba Med Ctr, Div Pediat Gastroenterol & Nutr, IL-52661 Tel Hashomer, Israel

[12] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel

[13] Hannover Med Sch, Dept Pediat Hematol & Oncol, D-30625 Hannover, Germany

[14] Childrens Natl Med Ctr, Dept Gastroenterol, Washington, DC USA

[15] Univ Michigan, Div Pediat Hematol & Oncol, Ann Arbor, MI 48109 USA

[16] Univ Fed Minas Gerais, Hosp Clin, BR-30130100 Belo Horizonte, MG, Brazil

[17] McMaster Childrens Hosp, Div Gastroenterol, Hamilton, ON L8N 3Z5, Canada

[18] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[19] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA

[20] Univ Manchester, Fac Life Sci, Manchester M13 9PL, Lancs, England

[21] Univ Munich, Dr von Hauner Childrens Hosp, D-80337 Munich, Germany

[22] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA

来源：

IMMUNITY | 2014年 / 40卷 / 05期

关键词：

INFLAMMATORY-BOWEL-DISEASE; DENDRITIC CELLS; T-CELLS; LY6C(HI) MONOCYTES; IL-10; MICE; DIFFERENTIATION; COLITIS; SUPPRESSION; HOMEOSTASIS;

D O I：

10.1016/j.immuni.2014.03.011

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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 T cells, was critical for regulating mucosal homeostasis. Following wild-type (WT) CD4(+) T cell 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(+) T cells 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.

引用

页码：706 / 719

页数：14

共 48 条

[1] Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6Chi monocyte precursors [J].

Bain, C. C. ;

Scott, C. L. ;

Uronen-Hansson, H. ;

Gudjonsson, S. ;

Jansson, O. ;

Grip, O. ;

Guilliams, M. ;

Malissen, B. ;

Agace, W. W. ;

Mowat, A. Mc I. .

MUCOSAL IMMUNOLOGY, 2013, 6 (03) :498-510

[2] Defective IL10 Signaling Defi ning a Subgroup of Patients With Inflammatory Bowel Disease [J].

Begue, Bernadette ;

Verdier, Julien ;

Rieux-Laucat, Frederic ;

Goulet, Olivier ;

Morali, Alain ;

Canioni, Danielle ;

Hugot, Jean-Pierre ;

Daussy, Cecile ;

Verkarre, Virginie ;

Pigneur, Benedicte ;

Fischer, Alain ;

Klein, Christoph ;

Cerf-Bensussan, Nadine ;

Ruemmele, Frank M. .

AMERICAN JOURNAL OF GASTROENTEROLOGY, 2011, 106 (08) :1544-1555

[3] Immunoregulation of dendritic cells by IL-10 is mediated through suppression of the PI3K/Akt pathway and of IκB kinase activity [J].

Bhattacharyya, S ;

Sen, P ;

Wallet, M ;

Long, B ;

Baldwin, AS ;

Tisch, R .

BLOOD, 2004, 104 (04) :1100-1109

[4] Interleukin-10 Signaling in Regulatory T Cells Is Required for Suppression of Th17 Cell-Mediated Inflammation [J].

Chaudhry, Ashutosh ;

Samstein, Robert M. ;

Treuting, Piper ;

Liang, Yuqiong ;

Pils, Marina C. ;

Heinrich, Jan-Michael ;

Jack, Robert S. ;

Wunderlich, F. Thomas ;

Bruening, Jens C. ;

Mueller, Werner ;

Rudensky, Alexander Y. .

IMMUNITY, 2011, 34 (04) :566-578

[5] IL-1β mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4+ Th17 cells [J].

Coccia, Margherita ;

Harrison, Oliver J. ;

Schiering, Chris ;

Asquith, Mark J. ;

Becher, Burkhard ;

Powrie, Fiona ;

Maloy, Kevin J. .

JOURNAL OF EXPERIMENTAL MEDICINE, 2012, 209 (09) :1595-1609

[6] Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses [J].

Denning, Timothy L. ;

Wang, Yi-Chong ;

Patel, Seema R. ;

Williams, Ifor R. ;

Pulendran, Bali .

NATURE IMMUNOLOGY, 2007, 8 (10) :1086-1094

[7] Clinical outcome in IL-10-and IL-10 receptor-deficient patients with or without hematopoietic stem cell transplantation [J].

Engelhardt, Karin R. ;

Shah, Neil ;

Faizura-Yeop, Intan ;

Uygun, Dilara F. Kocacik ;

Frede, Natalie ;

Muise, Aleixo M. ;

Shteyer, Eyal ;

Filiz, Serkan ;

Chee, Ronnie ;

Elawad, Mamoun ;

Hartmann, Britta ;

Arkwright, Peter D. ;

Dvorak, Christopher ;

Klein, Christoph ;

Puck, Jennifer M. ;

Grimbacher, Bodo ;

Glocker, Erik-Oliver .

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 2013, 131 (03) :825-+

[8]

FIORENTINO DF, 1991, J IMMUNOL, V147, P3815

[9] PD-L1 regulates the development, maintenance, and function of induced regulatory T cells [J].

Francisco, Loise M. ;

Salinas, Victor H. ;

Brown, Keturah E. ;

Vanguri, Vijay K. ;

Freeman, Gordon J. ;

Kuchroo, Vijay K. ;

Sharpe, Arlene H. .

JOURNAL OF EXPERIMENTAL MEDICINE, 2009, 206 (13) :3015-3029

[10] Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility [J].

Franke, Andre ;

Balschun, Tobias ;

Karlsen, Tom H. ;

Sventoraityte, Jurgita ;

Nikolaus, Susanna ;

Mayr, Gabriele ;

Domingues, Francisco S. ;

Albrecht, Mario ;

Nothnagel, Michael ;

Ellinghaus, David ;

Sina, Christian ;

Onnie, Clive M. ;

Weersma, Rinse K. ;

Stokkers, Pieter C. F. ;

Wijmenga, Cisca ;

Gazouli, Maria ;

Strachan, David ;

McArdle, Wendy L. ;

Vermeire, Severine ;

Rutgeerts, Paul ;

Rosenstiel, Philip ;

Krawczak, Michael ;

Vatn, Morten H. ;

Mathew, Christopher G. ;

Schreiber, Stefan .

NATURE GENETICS, 2008, 40 (11) :1319-1323

← 1 2 3 4 5 →