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      Canonical Wnt Signaling in CD11c+ APCs Regulates Microbiota-Induced Inflammation and Immune Cell Homeostasis in the Colon

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          Abstract

          <p class="first" id="P1">Aberrant Wnt/β-catenin signaling occurs in several inflammatory diseases including inflammatory bowel disease (IBD) and IBD-associated colon carcinogenesis. However, its role in shaping mucosal immune responses to commensals in the gut remains unknown. Here, we investigated the importance of canonical Wnt signaling in CD11c <sup>+</sup> antigen-presenting cells (APCs) in controlling intestinal inflammation. Using a mouse model of ulcerative colitis, we demonstrated that canonical Wnt signaling in intestinal CD11c <sup>+</sup> APCs controls intestinal inflammation by imparting an anti-inflammatory phenotype. Genetic deletion of Wnt co-receptors, low-density lipoprotein receptor-related protein 5 and 6 (LRP5/6) in CD11c <sup>+</sup> APCs in mice (LRP5/6 <sup>ΔCD11c</sup> mice) resulted in enhanced intestinal inflammation with increased histopathological severity of colonic tissue. This was due to microbiota-dependent increased production of pro-inflammatory cytokines and decreased expression of immune regulatory factors such as IL-10, RA and IDO. Mechanistically, loss of LRP5/6-mediated signaling in CD11c <sup>+</sup> APCs resulted in altered microflora and T cell homeostasis. Furthermore, our study demonstrates that conditional activation of β-catenin in CD11c <sup>+</sup> APCs in LRP5/6 <sup>ΔCD11c</sup> mice resulted in reduced intestinal inflammation with decreased histopathological severity of colonic tissue. These results reveal a mechanism by which intestinal APCs control intestinal inflammation and immune homeostasis via the canonical Wnt signaling pathway. </p>

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          Notch–RBP-J signaling controls the homeostasis of CD8− dendritic cells in the spleen

          Signaling through Notch receptors and their transcriptional effector RBP-J is essential for lymphocyte development and function, whereas its role in other immune cell types is unclear. We tested the function of the canonical Notch–RBP-J pathway in dendritic cell (DC) development and maintenance in vivo. Genetic inactivation of RBP-J in the bone marrow did not preclude DC lineage commitment but caused the reduction of splenic DC fraction. The inactivation of RBP-J in DCs using a novel DC-specific deleter strain caused selective loss of the splenic CD8− DC subset and reduced the frequency of cytokine-secreting CD8− DCs after challenge with Toll-like receptor ligands. In contrast, other splenic DC subsets and DCs in the lymph nodes and tissues were unaffected. The RBP-J–deficient splenic CD8− DCs were depleted at the postprogenitor stage, exhibited increased apoptosis, and lost the expression of the Notch target gene Deltex1. In the spleen, CD8− DCs were found adjacent to cells expressing the Notch ligand Delta-like 1 in the marginal zone (MZ). Thus, canonical Notch–RBP-J signaling controls the maintenance of CD8− DCs in the splenic MZ, revealing an unexpected role of the Notch pathway in the innate immune system.
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            Homeostasis and inflammation in the intestine.

            The gut is home to our largest collection of microbes. The ability of the immune system to coevolve with the microbiota during postnatal life allows the host and microbiota to coexist in a mutually beneficial relationship. Failure to achieve or maintain equilibrium between a host and its microbiota has negative consequences for both intestinal and systemic health. In this Review, we consider the many cellular and molecular methods by which inflammatory responses are regulated to maintain intestinal homeostasis and the disease states that can ensue when this balance is lost. 2010 Elsevier Inc. All rights reserved.
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              CD4(+) lymphoid tissue-inducer cells promote innate immunity in the gut.

              Fetal CD4(+) lymphoid tissue inducer (LTi) cells play a critical role in the development of lymphoid tissues. Recent studies identified that LTi cells persist in adults and are related to a heterogeneous population of innate lymphoid cells that have been implicated in inflammatory responses. However, whether LTi cells contribute to protective immunity remains poorly defined. We demonstrate that after infection with Citrobacter rodentium, CD4(+) LTi cells were a dominant source of interleukin-22 (IL-22) early during infection. Infection-induced CD4(+) LTi cell responses were IL-23 dependent, and ablation of IL-23 impaired innate immunity. Further, depletion of CD4(+) LTi cells abrogated infection-induced expression of IL-22 and antimicrobial peptides, resulting in exacerbated host mortality. LTi cells were also found to be essential for host protective immunity in lymphocyte-replete hosts. Collectively these data demonstrate that adult CD4(+) LTi cells are a critical source of IL-22 and identify a previously unrecognized function for CD4(+) LTi cells in promoting innate immunity in the intestine. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                The Journal of Immunology
                J.I.
                The American Association of Immunologists
                0022-1767
                1550-6606
                April 23 2018
                May 01 2018
                May 01 2018
                March 30 2018
                : 200
                : 9
                : 3259-3268
                Article
                10.4049/jimmunol.1701086
                6019297
                29602775
                b6e46631-1398-434b-a1a5-0cbb176cb73d
                © 2018
                History

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