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IL-22-dependent dysbiosis and mononuclear phagocyte depletion contribute to steroid-resistant gut graft-versus-host disease in mice I

ABSTRACT: CD4+ and CD8+ T cells can reciprocally differentiate into Th/Tc1, Th/Tc17 and Th/Tc22. Although alloreactive Th/Tc1 cells play a critical role in initiating pathogenesis of gut acute graft-versus-host disease (Gut-aGVHD), the pathogenic T cells in steroid-resistant Gut-aGVHD (SR-Gut-aGVHD) remains unclear. Here, we show that in murine models of SR-Gut-aGVHD, the pathogenesis is associated with reduction of IFN-g+ Th/Tc1 and IL-17A+IL-22- Th/Tc17 but expansion of IL-17-IL-22+ Th/Tc22, particularly Tc22 cells. IL-22 from Th/Tc22 cells causes dysbiosis. Using a Gut-aGVHD model induced by alloreactive IFN-g-/- CD8+ T cells, we show that the Gut-aGVHD pathogenesis requires both dysbiosis and depletion of CX3CR1hi mononuclear phagocytes (MNP) that regulate intestinal bacterial translocation. Absence of IFN-g leads to preferential expansion of Tc22 that induce dysbiosis by augmenting RegIIIg production, and depletion of CX3CR1hi MNP via its PD-1 interaction with tissue PD-L1. Interestingly, SR-Gut-aGVHD is also associated with depletion of CX3CR1hi MNP that reduces expansion of Tc22 under steroid treatment. Our studies indicate that expansion of Th/Tc22, dysbiosis, and depletion of CX3CR1hi MNP cells play critical roles in SR-Gut-aGVHD pathogenesis. These results provide new avenue towards studies in patients and call for caution in clinical testing of IL-22 agonists or IFN-g antagonist in patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE159031 | GEO | 2020/12/27

REPOSITORIES: GEO

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IL-22-dependent dysbiosis and mononuclear phagocyte depletion contribute to steroid-resistant gut graft-versus-host disease in mice II

Project description:CD4+ and CD8+ T cells can reciprocally differentiate into Th/Tc1, Th/Tc17 and Th/Tc22. Although alloreactive Th/Tc1 cells play a critical role in initiating pathogenesis of gut acute graft-versus-host disease (Gut-aGVHD), the pathogenic T cells in steroid-resistant Gut-aGVHD (SR-Gut-aGVHD) remains unclear. Here, we show that in murine models of SR-Gut-aGVHD, the pathogenesis is associated with reduction of IFN-g+ Th/Tc1 and IL-17A+IL-22- Th/Tc17 cells but expansion of IL-17-IL-22+ Th/Tc22, particularly Tc22 cells. The IL-22 from Th/Tc22 cells causes dysbiosis.

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Macrophage-restricted Interleukin-10 receptor-, but not IL-10 deficiency causes severe spontaneous colitis

Project description:Interleukin-10 (IL-10) is a pleiotropic anti-inflammatory cytokine produced and sensed by most hematopoietic cells. Genome wide association studies and experimental animal models point at a central role of the IL-10 axis in Inflammatory Bowel Diseases. Here we investigated the importance of intestinal macrophage production of IL-10 and their IL-10 exposure, as well as the existence of an IL-10-based autocrine regulatory loop in the gut. Specifically, we generated mice harboring IL-10 or IL-10 receptor (IL-10R?) mutations in intestinal lamina propria-resident chemokine receptor CX3CR1hi-expressingmacrophages. We found macrophage-derived IL-10 dispensable for gut homeostasis and maintenance of colonic T regulatory cells. In contrast, loss of IL-10 receptor expression impaired the critical conditioning of these monocyte-derived macrophages, but resulted in spontaneous development of severe colitis. Collectively, our results highlight IL-10 as a critical homeostatic macrophage-conditioning factor in the colon and define intestinal CX3CR1hi macrophages as a decisive factor that determines gut health or inflammation. Microarray of resident macrophages sorted from colons of Interleukin-10 deficeint mice and macrophage-restricted interleukin-10 receptor deficient mice versus colonic resident macrophages of wild type mice

2014-05-09 | E-GEOD-56444 | biostudies-arrayexpress

Macrophage-restricted Interleukin-10 receptor-, but not IL-10 deficiency causes severe spontaneous colitis

Project description:Interleukin-10 (IL-10) is a pleiotropic anti-inflammatory cytokine produced and sensed by most hematopoietic cells. Genome wide association studies and experimental animal models point at a central role of the IL-10 axis in Inflammatory Bowel Diseases. Here we investigated the importance of intestinal macrophage production of IL-10 and their IL-10 exposure, as well as the existence of an IL-10-based autocrine regulatory loop in the gut. Specifically, we generated mice harboring IL-10 or IL-10 receptor (IL-10Rα) mutations in intestinal lamina propria-resident chemokine receptor CX3CR1hi-expressingmacrophages. We found macrophage-derived IL-10 dispensable for gut homeostasis and maintenance of colonic T regulatory cells. In contrast, loss of IL-10 receptor expression impaired the critical conditioning of these monocyte-derived macrophages, but resulted in spontaneous development of severe colitis. Collectively, our results highlight IL-10 as a critical homeostatic macrophage-conditioning factor in the colon and define intestinal CX3CR1hi macrophages as a decisive factor that determines gut health or inflammation.

2014-05-09 | GSE56444 | GEO

Project description:Steroid-resistant gut graft-versus-host disease results from expansion of Th/Tc22, dysbiosis, and depletion of CX3CR1hi phagocytes

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Gut-Resident IL10+CX3CR1hi Macrophages Induce Tertiary Lymphoid Structures and IgA Response in Situ

Project description:Gut resident IL10+CX3CR1hi macrophages drive development of mucosal tertiary lymphoid structures that serve as ectopic site of the IgA response to enteric infection.

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Lipocalin-2 expression identifies an immuno-regulatory intestinal neutrophil population during GVHD

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Gene expression on in vitro T cells activated with IL-21

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2014-03-04 | GSE55509 | GEO

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2021-05-18 | GSE155172 | GEO

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