254
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      CX 3CR1 + mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Intestinal CX 3CR1 + mononuclear phagocytes regulate ILC3 in vivo in response to colitis associated microbial signals.

          Abstract

          Interleukin (IL)-22–producing group 3 innate lymphoid cells (ILC3) promote mucosal healing and maintain barrier integrity, but how microbial signals are integrated to regulate mucosal protection offered by these cells remains unclear. Here, we show that in vivo depletion of CX 3CR1 + mononuclear phagocytes (MNPs) resulted in more severe colitis and death after infection with Citrobacter rodentium. This phenotype was rescued by exogenous IL-22, which was endogenously produced by ILC3 in close spatial proximity to CX 3CR1 + MNPs that were dependent on MyD88 signaling. CX 3CR1 + MNPs from both mouse and human tissue produced more IL-23 and IL-1β than conventional CD103 + dendritic cells (cDCs) and were more efficient than cDCs in supporting IL-22 production in ILC3 in vitro and in vivo. Further, colonic ILC3 from patients with mild to moderate ulcerative colitis or Crohn’s disease had increased IL-22 production. IBD-associated SNP gene set analysis revealed enrichment for genes selectively expressed in human intestinal MNPs. The product of one of these, TL1A, potently enhanced IL-23– and IL-1β-induced production of IL-22 and GM-CSF by ILC3. Collectively, these results reveal a critical role for CX 3CR1 + mononuclear phagocytes in integrating microbial signals to regulate colonic ILC3 function in IBD.

          Related collections

          Most cited references31

          • Record: found
          • Abstract: found
          • Article: not found

          Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity.

          Although in vitro observations suggest that cross-presentation of antigens is mediated primarily by CD8alpha+ dendritic cells, in vivo analysis has been hampered by the lack of systems that selectively eliminate this cell lineage. We show that deletion of the transcription factor Batf3 ablated development of CD8alpha+ dendritic cells, allowing us to examine their role in immunity in vivo. Dendritic cells from Batf3-/- mice were defective in cross-presentation, and Batf3-/- mice lacked virus-specific CD8+ T cell responses to West Nile virus. Importantly, rejection of highly immunogenic syngeneic tumors was impaired in Batf3-/- mice. These results suggest an important role for CD8alpha+ dendritic cells and cross-presentation in responses to viruses and in tumor rejection.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain.

            Interleukin-12 (IL-12) is a heterodimeric molecule composed of p35 and p40 subunits. Analyses in vitro have defined IL-12 as an important factor for the differentiation of naive T cells into T-helper type 1 CD4+ lymphocytes secreting interferon-gamma (refs 1, 2). Similarly, numerous studies have concluded that IL-12 is essential for T-cell-dependent immune and inflammatory responses in vivo, primarily through the use of IL-12 p40 gene-targeted mice and neutralizing antibodies against p40. The cytokine IL-23, which comprises the p40 subunit of IL-12 but a different p19 subunit, is produced predominantly by macrophages and dendritic cells, and shows activity on memory T cells. Evidence from studies of IL-23 receptor expression and IL-23 overexpression in transgenic mice suggest, however, that IL-23 may also affect macrophage function directly. Here we show, by using gene-targeted mice lacking only IL-23 and cytokine replacement studies, that the perceived central role for IL-12 in autoimmune inflammation, specifically in the brain, has been misinterpreted and that IL-23, and not IL-12, is the critical factor in this response. In addition, we show that IL-23, unlike IL-12, acts more broadly as an end-stage effector cytokine through direct actions on macrophages.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function.

              MyD88, originally isolated as a myeloid differentiation primary response gene, is shown to act as an adaptor in interleukin-1 (IL-1) signaling by interacting with both the IL-1 receptor complex and IL-1 receptor-associated kinase (IRAK). Mice generated by gene targeting to lack MyD88 have defects in T cell proliferation as well as induction of acute phase proteins and cytokines in response to IL-1. Increases in interferon-gamma production and natural killer cell activity in response to IL-18 are abrogated. In vivo Th1 response is also impaired. Furthermore, IL-18-induced activation of NF-kappaB and c-Jun N-terminal kinase (JNK) is blocked in MyD88-/- Th1-developing cells. Taken together, these results demonstrate that MyD88 is a critical component in the signaling cascade that is mediated by IL-1 receptor as well as IL-18 receptor.
                Bookmark

                Author and article information

                Journal
                J Exp Med
                J. Exp. Med
                jem
                jem
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                28 July 2014
                : 211
                : 8
                : 1571-1583
                Affiliations
                [1 ]The Kimmel Center for Biology and Medicine of the Skirball Institute and [2 ]Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016
                [3 ]The Jill Roberts Center for IBD, Department of Medicine, Weill-Cornell Medical College, New York, NY 10021
                [4 ]Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032
                [5 ]Center for Genomics and Systems Biology, Department of Biology; and [6 ]Courant Institute of Mathematical Sciences, Computer Science Department, New York University, New York, NY10003
                Author notes
                CORRESPONDENCE Randy S. Longman: ral2006@ 123456med.cornell.edu OR Dan R. Littman: dan.littman@ 123456med.nyu.edu

                R.S. Longman and G.E. Diehl contributed equally to this paper.

                J.R. Huh’s present address is University of Massachusetts Medical School, Worcester, MA 01605.

                A. Swaminath’s present address is Lennox Hill Hospital, New York, NY 10075.

                Article
                20140678
                10.1084/jem.20140678
                4113938
                25024136
                230035dc-d8bc-4406-9c4b-ba6a1dba3af5
                © 2014 Longman et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

                History
                : 9 April 2014
                : 18 June 2014
                Categories
                303
                Article

                Medicine
                Medicine

                Comments

                Comment on this article