The monocyte-macrophage axis in the intestine
TL;DR: Residents and proinflammatory intestinal Mϕ both derive from Ly6Chi blood monocytes, and monocyte differentiation is disrupted by inflammation resulting in the accumulation of proinflammatory cells.
About: This article is published in Cellular Immunology.The article was published on 2014-09-01 and is currently open access. It has received 126 citations till now. The article focuses on the topics: Intestinal mucosa & Macrophage.
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28,685 citations
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TL;DR: Schulz et al. as discussed by the authors investigated whether adult macrophages all share a common developmental origin and found that a population of yolk-sac-derived, tissue-resident macophages was able to develop and persist in adult mice in the absence of hematopoietic stem cells.
Abstract: Macrophage Development Rewritten Macrophages provide protection against a wide variety of infections and critically shape the inflammatory environment in many tissues. These cells come in many flavors, as determined by differences in gene expression, cell surface phenotype and specific function. Schulz et al. (p. 86, published online 22 March) investigated whether adult macrophages all share a common developmental origin. Immune cells, including most macrophages, are widely thought to arise from hematopoietic stem cells (HSCs), which require the transcription factor Myb for their development. Analysis of Myb-deficient mice revealed that a population of yolk-sac–derived, tissue-resident macrophages was able to develop and persist in adult mice in the absence of HSCs. Importantly, yolk sac–derived macrophages also contributed substantially to the tissue macrophage pool even when HSCs were present. In mice, a population of tissue-resident macrophages arises independently of bone marrow–derived stem cells. Macrophages and dendritic cells (DCs) are key components of cellular immunity and are thought to originate and renew from hematopoietic stem cells (HSCs). However, some macrophages develop in the embryo before the appearance of definitive HSCs. We thus reinvestigated macrophage development. We found that the transcription factor Myb was required for development of HSCs and all CD11bhigh monocytes and macrophages, but was dispensable for yolk sac (YS) macrophages and for the development of YS-derived F4/80bright macrophages in several tissues, such as liver Kupffer cells, epidermal Langerhans cells, and microglia—cell populations that all can persist in adult mice independently of HSCs. These results define a lineage of tissue macrophages that derive from the YS and are genetically distinct from HSC progeny.
1,673 citations
TL;DR: This Opinion article suggests that the mononuclear phagocyte system can be classified primarily by their ontogeny and secondarily by their location, function and phenotype, which permits a more robust classification during both steady-state and inflammatory conditions.
Abstract: The mononuclear phagocyte system (MPS) has historically been categorized into monocytes, dendritic cells and macrophages on the basis of functional and phenotypical characteristics. However, considering that these characteristics are often overlapping, the distinction between and classification of these cell types has been challenging. In this Opinion article, we propose a unified nomenclature for the MPS. We suggest that these cells can be classified primarily by their ontogeny and secondarily by their location, function and phenotype. We believe that this system permits a more robust classification during both steady-state and inflammatory conditions, with the benefit of spanning different tissues and across species.
1,404 citations
TL;DR: It is found that embryonic precursor cells seeded the intestinal mucosa and demonstrated extensive in situ proliferation during the neonatal period, but these cells did not persist in the intestine of adult mice and were replaced around the time of weaning by the chemokine receptor CCR2–dependent influx of Ly6Chi monocytes that differentiated locally into mature, anti-inflammatory macrophages.
Abstract: The paradigm that macrophages that reside in steady-state tissues are derived from embryonic precursors has never been investigated in the intestine, which contains the largest pool of macrophages. Using fate-mapping models and monocytopenic mice, together with bone marrow chimera and parabiotic models, we found that embryonic precursor cells seeded the intestinal mucosa and demonstrated extensive in situ proliferation during the neonatal period. However, these cells did not persist in the intestine of adult mice. Instead, they were replaced around the time of weaning by the chemokine receptor CCR2-dependent influx of Ly6C(hi) monocytes that differentiated locally into mature, anti-inflammatory macrophages. This process was driven largely by the microbiota and had to be continued throughout adult life to maintain a normal intestinal macrophage pool.
812 citations
TL;DR: It is demonstrated that GPBAR1 gene ablation enhanced the recruitment of classically activated macrophages in the colonic lamina propria and worsened the severity of inflammation, and its activation promotes a IL-10–dependent shift toward an alternatively activated phenotype.
Abstract: GPBAR1 (TGR5 or M-BAR) is a G protein-coupled receptor for secondary bile acids that is highly expressed in monocytes/macrophages. In this study, we aimed to determine the role of GPBAR1 in mediating leukocyte trafficking in chemically induced models of colitis and investigate the therapeutic potential of BAR501, a small molecule agonist for GPBAR1. These studies demonstrated that GPBAR1 gene ablation enhanced the recruitment of classically activated macrophages in the colonic lamina propria and worsened the severity of inflammation. In contrast, GPBAR1 activation by BAR501 reversed intestinal inflammation in the trinitrobenzenesulfonic acid and oxazolone models by reducing the trafficking of Ly6C+ monocytes from blood to intestinal mucosa. Exposure to BAR501 shifted intestinal macrophages from a classically activated (CD11b+, CCR7+, F4/80-) to an alternatively activated (CD11b+, CCR7-, F4/80+) phenotype, reduced the expression of inflammatory genes (TNF-α, IFN-γ, IL-1β, IL-6, and CCL2 mRNAs), and attenuated the wasting syndrome and severity of colitis (≈70% reduction in the Colitis Disease Activity Index). The protective effect was lost in Gpbar1-/- mice. Exposure to BAR501 increased the colonic expression of IL-10 and TGF-β mRNAs and the percentage of CD4+/Foxp3+ cells. The beneficial effects of BAR501 were lost in Il-10-/- mice. In a macrophage cell line, regulation of IL-10 by BAR501 was GPBAR1 dependent and was mediated by the recruitment of CREB to its responsive element in the IL-10 promoter. In conclusion, GPBAR1 is expressed in circulating monocytes and colonic macrophages, and its activation promotes a IL-10-dependent shift toward an alternatively activated phenotype. The targeting of GPBAR1 may offer therapeutic options in inflammatory bowel diseases.
177 citations
Cites background from "The monocyte-macrophage axis in the..."
...These findings provide further support that GPBAR1 could be exploited for the development of gut-specific therapies for IBDs without dampening the systemic immune system....
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...Because glucocorticoids are widely used in the treatment of IBDs, we next investigated how BAR501 compares with dexamethasone, a synthetic glucocorticoid, in the treatment of TNBS colitis....
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...IBDs have traditionally been treated with nonspecific immunosuppressive drugs (e.g., corticosteroids or azathioprine), anti-inflammatory agents (e.g., 5-aminosalicylic acid), and, more recently, with anti–TNF-a agents (3)....
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...The present observations pave the way for the development of GPBAR1-based anti-inflammatory agents for the treatment of IBDs....
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...Because macrophages are one of the most abundant leukocytes in the intestinal mucosa and are implicated in the pathogenesis of IBDs (23, 24), we have investigated whether treatment with BAR501 attenuates the inflammation and immune dysfunction in BALB/c mice treated with TNBS and modulates macrophage recruitment/activity....
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References
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Journal Article•
28,685 citations
"The monocyte-macrophage axis in the..." refers background in this paper
...CCL2 have markedly reduced intestinal m/ pools [7,52]....
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...recruitment mechanism, as intestinal m/ are not entirely absent in steady state CCR2 / and CCL2 / mice [7,52]....
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TL;DR: The results indicate that the bowel inflammation in the mutants originates from uncontrolled immune responses stimulated by enteric antigens and that IL-10 is an essential immunoregulator in the intestinal tract.
4,196 citations
TL;DR: Using a murine adoptive transfer system to probe monocyte homing and differentiation in vivo, two functional subsets among murine blood monocytes are identified: a short-lived CX(3)CR1(lo)CCR2(+)Gr1(+) subset that is actively recruited to inflamed tissues and a CX (3) CR1(hi)CCS1-dependent recruitment to noninflamed tissues.
3,307 citations
"The monocyte-macrophage axis in the..." refers background in this paper
...The larger subset is Ly6C (Gr-1) and expresses high levels of CCR2 and CD62L, but low levels of CX3CR1 [33]....
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...They express the CSF1R (CD115) and two subsets can be identified on the basis of Ly6C (or Gr-1) expression [33]....
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...that replenished steady state macrophage populations [33]....
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TL;DR: A new mechanism for bacterial uptake in the mucosa tissues that is mediated by dendritic cells (DCs) is reported, which open the tight junctions between epithelial cells, send dendrites outside the epithelium and directly sample bacteria.
Abstract: Penetration of the gut mucosa by pathogens expressing invasion genes is believed to occur mainly through specialized epithelial cells, called M cells, that are located in Peyer's patches. However, Salmonella typhimurium that are deficient in invasion genes encoded by Salmonella pathogenicity island 1 (SPI1) are still able to reach the spleen after oral administration. This suggests the existence of an alternative route for bacterial invasion, one that is independent of M cells. We report here a new mechanism for bacterial uptake in the mucosa tissues that is mediated by dendritic cells (DCs). DCs open the tight junctions between epithelial cells, send dendrites outside the epithelium and directly sample bacteria. In addition, because DCs express tight-junction proteins such as occludin, claudin 1 and zonula occludens 1, the integrity of the epithelial barrier is preserved.
2,463 citations
TL;DR: A fate-mapping study of the murine monocyte and macrophage compartment taking advantage of constitutive and conditional CX(3)CR1 promoter-driven Cre recombinase expression is reported, establishing that short-lived Ly6C(+) monocytes constitute obligatory steady-state precursors of blood-resident Ly 6C(-) cells and that the abundance of Ly6 C(+) blood monocytes dynamically controls the circulation lifespan of their progeny.
2,302 citations