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• W2000647799 abstract "Dendritic cells (DCs) arise from dedicated precursors and monocytes; however, the impact of these differential origins remain unclear. In this issue of Immunity, Siddiqui et al., 2010Siddiqui K.R.R. Laffont S. Powrie F. Immunity. 2010; 32 (this issue): 557-567Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar describe a population of colitogenic monocyte-derived DCs that propagate intestinal inflammation. Dendritic cells (DCs) arise from dedicated precursors and monocytes; however, the impact of these differential origins remain unclear. In this issue of Immunity, Siddiqui et al., 2010Siddiqui K.R.R. Laffont S. Powrie F. Immunity. 2010; 32 (this issue): 557-567Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar describe a population of colitogenic monocyte-derived DCs that propagate intestinal inflammation. The human intestinal tract covers the area of a soccer pitch lined by a single layer of columnar epithelial cells, which forms the barrier between the gut lumen and the host connective tissue. On top of its constant exposure to dietary and environmental antigens, the intestine harbors an estimated 1014 commensal bacteria. It is in this unique, complex and vulnerable setting that inflammatory bowel diseases (IBDs), such as Crohn's disease and ulcerative colitis, occur in genetically predisposed individuals. Moreover, the intestinal tract presents also a major site of pathogen entry requiring an immune defense. To cope with these challenges, the mammalian organism has evolved robustly balanced immune mechanisms that provide protection against invading pathogens, yet prevent detrimental collateral damage by inflammatory responses against the commensal microbiota and food antigens. In this issue of Immunity, Siddiqui et al., 2010Siddiqui K.R.R. Laffont S. Powrie F. Immunity. 2010; 32 (this issue): 557-567Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar identify a population of dendritic cells (DCs) that mediate the inflammatory immune responses (Figure 1). Recent findings indicate that intestinal mononuclear phagocytes, comprising DCs and macrophages, are crucial for maintaining intestinal homeostasis. Understanding how these cells interact with the triad of microbiota, lymphocytes, and the epithelium to shape intestinal immune responses will be important for identifying therapeutic IBD targets. The intestinal mononuclear phagocyte compartment of the mouse in the steady state is now mapped in fair detail. Murine intestinal macrophages and DCs can be found as resident cells in gut-associated lymphoid tissue (GALT), including isolated lymphoid follicles (ILFs), Peyer's patches (PPs), and the gut-draining mesenteric lymph nodes (MsnLNs). Moreover, mononuclear phagocytes, and in particular DCs, are also highly abundant in the loose connective tissue underlying the columnar epithelial cell layer, the lamina propria. As in other tissues, intestinal mononuclear phagocytes have also been subdivided according to characteristic surface marker expression patterns, in this case the integrins CD11c, CD11b, and CD103, as well as the chemokine receptor CX3CR1. Although these seemingly arbitrary phenotypic categorizations help researchers to communicate, the subdivisions have recently been substantiated by the discovery of discrete origins of the intestinal DC subsets. All peripheral mononuclear phagocytes are currently considered derived from a dedicated bone marrow resident precursor cell, the so-called macrophage-DC precursors (MDPs). However, in the bone marrow MDPs give rise to two circulating DC precursors. In steady state, lamina propria-resident CX3CR1+ DCs that can uniquely penetrate the gut epithelium to sense or sample gut content are generated from circulating blood monocytes, specifically the Ly6Chi monocyte subset (Bogunovic et al., 2009Bogunovic M. Ginhoux F. Helft J. Shang L. Hashimoto D. Greter M. Liu K. Jakubzick C. Ingersoll M.A. Leboeuf M. et al.Immunity. 2009; 31: 513-525Abstract Full Text Full Text PDF PubMed Scopus (650) Google Scholar, Varol et al., 2009aVarol C. Vallon-Eberhard A. Elinav E. Aychek T. Shapira Y. Luche H. Fehling H.J. Hardt W.D. Shakhar G. Jung S. Immunity. 2009; 31: 502-512Abstract Full Text Full Text PDF PubMed Scopus (548) Google Scholar). In contrast, lamina propria-resident CD103+ CD11b+ DCs derive—like their splenic counterpart, the classical DCs (cDCs), and probably also GALT-resident CD103+ CD11b− DCs—from recently described dedicated circulating DC precursors (pre-cDCs [Liu et al., 2009Liu K. Victora G.D. Schwickert T.A. Guermonprez P. Meredith M.M. Yao K. Chu F.F. Randolph G.J. Rudensky A.Y. Nussenzweig M. Science. 2009; 324: 392-397Crossref PubMed Scopus (285) Google Scholar]). Importantly, recent data suggest that only CD103+ CD11b+ DCs, but not CX3CR1+ DCs, migrate in a CCR7-dependent manner to the mesenteric LNs to promote T cell polarization toward effector or regulatory fates (Schulz et al., 2009Schulz O. Jaensson E. Persson E.K. Liu X. Worbs T. Agace W.W. Pabst O. J. Exp. Med. 2009; 206: 3101-3114Crossref PubMed Scopus (505) Google Scholar). However, lamina propria CD103+ CD11b+ DCs seem to remember their upbringing, as they remain conditioned by the unique tissue environment of the lamina propria and the overlying lumen content-exposed epithel. Upon their arrival in the draining mesenteric LNs, CD103+ CD11b+ DCs are hence biased to support the induction of T regulatory cells and produce cytokine, such as TGF-β, thereby contributing to the immuno-suppressive steady-state gut environment. As compared to our understanding of mouse gut immune homeostasis that extends to the interplay of the commensal microbiota with the mucosal T cell compartment and T cell-dependent and -independent IgA production by B cells, the processes occurring in acute and chronic gut inflammation remain still a black box. Paradoxically, this is in stark contrast to the data available of the human intestinal landscape, in which most of our knowledge stems from the analysis of diseased tissue specimen isolated form IBD patients. Siddiqui et al., 2010Siddiqui K.R.R. Laffont S. Powrie F. Immunity. 2010; 32 (this issue): 557-567Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar shed light into the murine black box of gut inflammation. Specifically, Siddiqui et al. identified a population of E-cadherin+ DCs that accumulates in the colon and the mesenteric LNs of mice suffering from colitis. Interestingly though, the summoning of E-cadherin+ monocyte-drived DCs was restricted to T cell-driven colitis and the engagement of CD40 on innate cells, but did not occur in a merely innate Helicobacter hepaticus-driven colitis model. When taken into culture, E-cadherin+ DCs spontaneously produced substantially more colitogenic cytokines, such as IL-6 and IL-23, than conventional MsnLN DCs. Moreover, E-cadherin+ DCs also expressed a uniquely broad pattern of Toll-like receptors (TLRs) rendering them highly receptive for microbial products that could potentially exacerbate their activities. Finally, Siddiqui et al. showed that the transfer of bone marrow culture-derived E-cadherin+ DCs, but not E-cadherin− DCs into T cell-deficient (Rag-deficient) mice that had received a CD45RBhi T cell graft significantly worsened the colitis profile and boosted the expansion of Th17 cells. Interestingly, the authors provide furthermore both in vitro and in vivo evidence that the accumulation of these E-cadherin+ DCs is prevented by the regulatory cytokine TGF-β, as by transfer of T regulatory cells in the course of their protection from colitis. Collectively, these results highlight a key detrimental role of these E-cadherin+ DCs in the perpetuation of the chronic inflammatory process. Phenotypic characteristics and their chemokine receptor expression profile, i.e., the lack of CCR7 that is required for MsnLN homing, suggested to Siddiqui et al. that the E-cadherin+ DCs had not entered the LNs via the lymphatics, but rather were blood derived. Indeed, the authors directly corroborated this assumption by performing adoptive monocyte transfer experiments. Moreover, the results of these studies provide evidence that the colitogenic E-cadherin+ DCs are specifically derived from a particular Ly6C+ monocyte subset. On the basis of histological findings documenting massive cellular infiltrations, circulating blood monocytes have long been appreciated to play a prominent role in inflammation. However, only recently the study of these ephemeral cells in animal models is taking off because of seminal breakthroughs, such as the definition of the Ly6Chi and Ly6Clo monocyte subsets (Geissmann et al., 2003Geissmann F. Jung S. Littman D.R. Immunity. 2003; 19: 71-82Abstract Full Text Full Text PDF PubMed Scopus (2408) Google Scholar) and the development of novel experimental approaches that has allowed studying of the cells in a physiological context. The prime task of monocytes had long been considered the replenishment of the short-lived peripheral DC compartment. However, surprisingly, the in vivo studies revealed that these cells did in fact not give rise to what was considered classical DCs. Rather monocytes differentiated in the tissues into a distinct cell type, now termed monocyte-derived DCs (MoDCs) or “inflammatory DCs” (Shortman and Naik, 2007Shortman K. Naik S.H. Nat. Rev. Immunol. 2007; 7: 19-30Crossref PubMed Scopus (925) Google Scholar). A specific nonredundant function of the latter cells was first suggested by studies of the Pamer group, who showed that Ly6Chi monocytes differentiate in Listeria monocytogenes-infected spleens into TNF-and-iNOS-producing DCs (TIP-DCs), which critically contribute to bacterial clearance (Serbina et al., 2003Serbina N.V. Salazar-Mather T.P. Biron C.A. Kuziel W.A. Pamer E.G. Immunity. 2003; 19: 59-70Abstract Full Text Full Text PDF PubMed Scopus (872) Google Scholar). Moreover, Gunn and colleagues recently established that after their recruitment to inflamed lymph nodes, CCR2-expressing Ly6Chi monocytes turn into IL-12-secreting DCs that boost IFN-γ production by antiviral T cells (Nakano et al., 2009Nakano H. Lin K.L. Yanagita M. Charbonneau C. Cook D.N. Kakiuchi T. Gunn M.D. Nat. Immunol. 2009; 10: 394-402Crossref PubMed Scopus (255) Google Scholar). Notably, although originally termed “inflammatory” (Geissmann et al., 2003Geissmann F. Jung S. Littman D.R. Immunity. 2003; 19: 71-82Abstract Full Text Full Text PDF PubMed Scopus (2408) Google Scholar), Ly6Chi monocytes are far more versatile and do not only exhibit proinflammatory features. Rather, their activities are probably dictated by the tissue context they encounter upon extravasation (Varol et al., 2009bVarol C. Yona S. Jung S. Immunol. Cell Biol. 2009; 87: 30-38Crossref PubMed Scopus (98) Google Scholar). In fact, in absence of inflammation, Ly6Chi monocytes return from the blood to the bone marrow and convert into Ly6Clo monocytes that can serve as precursors of tissue macrophages. Moreover, in DC-depleted animals, Ly6Chi monocytes can replenish the entire CX3CR1+ lamina propria DC compartment while keeping gut homeostasis, as long as they are balanced by CD103+ DCs (Varol et al., 2009aVarol C. Vallon-Eberhard A. Elinav E. Aychek T. Shapira Y. Luche H. Fehling H.J. Hardt W.D. Shakhar G. Jung S. Immunity. 2009; 31: 502-512Abstract Full Text Full Text PDF PubMed Scopus (548) Google Scholar). Finally, emerging evidence indicates that—in particular under inflammatory conditions—monocytes exert important accessory roles to physiological processes in their own right, i.e., beyond their classical role as precursors of peripheral macrophages and DCs. This includes their involvement in healing processes at the myocard, the injured muscle, and spinal cord, as well as critical contributions to adult neovascularization in tumors and tissue remodeling (Varol et al., 2009bVarol C. Yona S. Jung S. Immunol. Cell Biol. 2009; 87: 30-38Crossref PubMed Scopus (98) Google Scholar). The importance of the study of Siddiqui et al. lies in the fact that the authors establish an intriguing link between monocytes and the perpetuation of chronic intestinal inflammation and thereby extend previous studies on monocyte-derived DCs (Nakano et al., 2009Nakano H. Lin K.L. Yanagita M. Charbonneau C. Cook D.N. Kakiuchi T. Gunn M.D. Nat. Immunol. 2009; 10: 394-402Crossref PubMed Scopus (255) Google Scholar, Serbina et al., 2003Serbina N.V. Salazar-Mather T.P. Biron C.A. Kuziel W.A. Pamer E.G. Immunity. 2003; 19: 59-70Abstract Full Text Full Text PDF PubMed Scopus (872) Google Scholar) to the clinically highly relevant setting of IBDs. Notably, the monocyte compartment is extremely short lived and plastic, and hence probably readily amenable to manipulation. The discovery of the detrimental role of monocyte-derived DCs in colitis might therefore open new avenues for therapeutic interventions, including the interference with monocyte recruitment, transient cell ablation, and modulation of the monocyte subset prevalence. An important question though remains: arguably the mere increase in production rate and shortening of bone marrow residency will modify the monocytes; however, does the inflammatory condition have a defined qualitative impact on the blood monocyte compartment? Or do circulating cells remain naive in the chronically inflamed organism and undistinguishable from the steady state until they reach the inflamed tissue? These and other questions should spur efforts to extend the study of mouse models of chronic disease and inflammation to the blood, as—to finish with Goethe—“Blood is a quite special kind of juice” (Faust I, 1808). E-Cadherin Marks a Subset of Inflammatory Dendritic Cells that Promote T Cell-Mediated ColitisSiddiqui et al.ImmunityApril 15, 2010In BriefDendritic cells (DCs) play a pivotal role in controlling the balance between tolerance and immunity in the intestine. Gut conditioned CD103+ DCs promote regulatory T (Treg) cell responses; however, little is known about DCs that drive inflammation in the intestine. Here, we show that monocyte-derived inflammatory DCs that express E-cadherin, the receptor for CD103, promote intestinal inflammation. E-cadherin+ DCs accumulated in the inflamed mesenteric lymph nodes and colon, had high expression of toll-like receptors, and produced colitogenic cytokines, such as IL-6 and IL-23, after activation. Full-Text PDF Open Access" @default.
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• W2000647799 title "Dendritic Cells: A Question of Upbringing" @default.
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