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

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2014 May 6

PMID 24792912

Citations 283

Authors

Dror S Shouval

Amlan Biswas

Jeremy A Goettel

Katelyn McCann

Evan Conaway

Naresh S Redhu

Ivan D Mascanfroni

Ziad Al Adham

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 Muller

J Rodrigo Mora

Francisco J Quintana

Christoph Klein

Aleixo M Muise

Bruce H Horwitz

Scott B Snapper

Affiliations

Soon will be listed here.

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 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.

Citing Articles

Antagonizing Il10 and Il4 signaling via intracerebral decoy receptor expression attenuates Aβ accumulation.

Koller E, McFarland K, Angelle C, Howard J, Ryu D, Dillon K Acta Neuropathol Commun. 2025; 13(1):51.

PMID: 40055831 PMC: 11887169. DOI: 10.1186/s40478-025-01968-3.

Alternate-day fasting differentially affects body composition, metabolic and immune response to fasting in male rats exposed to early-life adversity: Modulatory role of cafeteria diet.

Sagae S, Paz E, Zanardini B, Amaral A, Bronczek G, Koehler-Santos P PLoS One. 2025; 20(3):e0313103.

PMID: 40029907 PMC: 11875342. DOI: 10.1371/journal.pone.0313103.

Exosomes from adipose-derived stem cells accelerate wound healing by increasing the release of IL-33 from macrophages.

Wang Y, Ding H, Bai R, Li Q, Ren B, Lin P Stem Cell Res Ther. 2025; 16(1):80.

PMID: 39984984 PMC: 11846291. DOI: 10.1186/s13287-025-04203-x.

Genetic predisposition to Behcet's disease mediated by a IL10RA enhancer polymorphism.

Tan H, Zhong Z, Feng X, Luo X, Cao Q, Yang P Heliyon. 2025; 11(1):e41529.

PMID: 39844988 PMC: 11750533. DOI: 10.1016/j.heliyon.2024.e41529.

Mitochondria complex III-generated superoxide is essential for IL-10 secretion in macrophages.

Stoolman J, Grant R, Billingham L, Poor T, Weinberg S, Harding M Sci Adv. 2025; 11(4):eadu4369.

PMID: 39841842 PMC: 11753406. DOI: 10.1126/sciadv.adu4369.

References

Engelhardt K, Shah N, Faizura-Yeop I, Uygun D, Frede N, Muise A . Clinical outcome in IL-10- and IL-10 receptor-deficient patients with or without hematopoietic stem cell transplantation. J Allergy Clin Immunol. 2012; 131(3):825-30. DOI: 10.1016/j.jaci.2012.09.025. View

Zhang Y, Chung Y, Bishop C, Daugherty B, Chute H, Holst P . Regulation of T cell activation and tolerance by PDL2. Proc Natl Acad Sci U S A. 2006; 103(31):11695-700. PMC: 1544232. DOI: 10.1073/pnas.0601347103. View

Moran C, Walters T, Guo C, Kugathasan S, Klein C, Turner D . IL-10R polymorphisms are associated with very-early-onset ulcerative colitis. Inflamm Bowel Dis. 2012; 19(1):115-23. PMC: 3744177. DOI: 10.1002/ibd.22974. View

Guarda G, Braun M, Staehli F, Tardivel A, Mattmann C, Forster I . Type I interferon inhibits interleukin-1 production and inflammasome activation. Immunity. 2011; 34(2):213-23. DOI: 10.1016/j.immuni.2011.02.006. View

Spencer S, Di Marco F, Hooley J, Bauer M, Ryan A, Sordat B . The orphan receptor CRF2-4 is an essential subunit of the interleukin 10 receptor. J Exp Med. 1998; 187(4):571-8. PMC: 2212143. DOI: 10.1084/jem.187.4.571. View

Martinez F, Gordon S, Locati M, Mantovani A . Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J Immunol. 2006; 177(10):7303-11. DOI: 10.4049/jimmunol.177.10.7303. View

Glocker E, Kotlarz D, Boztug K, Gertz E, Schaffer A, Noyan F . Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med. 2009; 361(21):2033-45. PMC: 2787406. DOI: 10.1056/NEJMoa0907206. View

Medina-Contreras O, Geem D, Laur O, Williams I, Lira S, Nusrat A . CX3CR1 regulates intestinal macrophage homeostasis, bacterial translocation, and colitogenic Th17 responses in mice. J Clin Invest. 2011; 121(12):4787-95. PMC: 3226003. DOI: 10.1172/JCI59150. View

Zigmond E, Varol C, Farache J, Elmaliah E, Satpathy A, Friedlander G . Ly6C hi monocytes in the inflamed colon give rise to proinflammatory effector cells and migratory antigen-presenting cells. Immunity. 2012; 37(6):1076-90. DOI: 10.1016/j.immuni.2012.08.026. View

10.

Sabat R . IL-10 family of cytokines. Cytokine Growth Factor Rev. 2010; 21(5):315-24. DOI: 10.1016/j.cytogfr.2010.11.001. View

11.

Hedl M, Abraham C . Nod2-induced autocrine interleukin-1 alters signaling by ERK and p38 to differentially regulate secretion of inflammatory cytokines. Gastroenterology. 2012; 143(6):1530-43. PMC: 3618474. DOI: 10.1053/j.gastro.2012.08.048. View

12.

Parsa R, Andresen P, Gillett A, Mia S, Zhang X, Mayans S . Adoptive transfer of immunomodulatory M2 macrophages prevents type 1 diabetes in NOD mice. Diabetes. 2012; 61(11):2881-92. PMC: 3478537. DOI: 10.2337/db11-1635. View

13.

Franke A, McGovern D, Barrett J, Wang K, Radford-Smith G, Ahmad T . Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet. 2010; 42(12):1118-25. PMC: 3299551. DOI: 10.1038/ng.717. View

14.

Franke A, Balschun T, Karlsen T, Sventoraityte J, Nikolaus S, Mayr G . Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat Genet. 2008; 40(11):1319-23. DOI: 10.1038/ng.221. View

15.

Hadis U, Wahl B, Schulz O, Hardtke-Wolenski M, Schippers A, Wagner N . Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria. Immunity. 2011; 34(2):237-46. DOI: 10.1016/j.immuni.2011.01.016. View

16.

Bhattacharyya S, Sen P, Wallet M, Long B, Baldwin Jr A, Tisch R . Immunoregulation of dendritic cells by IL-10 is mediated through suppression of the PI3K/Akt pathway and of IkappaB kinase activity. Blood. 2004; 104(4):1100-9. DOI: 10.1182/blood-2003-12-4302. View

17.

Lasfar A, Abushahba W, Balan M, Cohen-Solal K . Interferon lambda: a new sword in cancer immunotherapy. Clin Dev Immunol. 2011; 2011:349575. PMC: 3235441. DOI: 10.1155/2011/349575. View

18.

Saraiva M, OGarra A . The regulation of IL-10 production by immune cells. Nat Rev Immunol. 2010; 10(3):170-81. DOI: 10.1038/nri2711. View

19.

Bain C, Scott C, Uronen-Hansson H, Gudjonsson S, Jansson O, Grip O . Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6Chi monocyte precursors. Mucosal Immunol. 2012; 6(3):498-510. PMC: 3629381. DOI: 10.1038/mi.2012.89. View

20.

Chaudhry A, Samstein R, Treuting P, Liang Y, Pils M, Heinrich J . Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity. 2011; 34(4):566-78. PMC: 3088485. DOI: 10.1016/j.immuni.2011.03.018. View