Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The . gov means it’s official. Federal government websites often end in . gov or . mil. Before sharing sensitive information, make sure you’re on a federal government site. VSports app下载.

Https

The site is secure V体育官网. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. .

. 2011 Dec;121(12):4787-95.
doi: 10.1172/JCI59150.

VSports手机版 - CX3CR1 regulates intestinal macrophage homeostasis, bacterial translocation, and colitogenic Th17 responses in mice

Oscar Medina-Contreras  1 , Duke Geem, Oskar Laur, Ifor R Williams, Sergio A Lira, Asma Nusrat, Charles A Parkos, Timothy L Denning
Affiliations

CX3CR1 regulates intestinal macrophage homeostasis, bacterial translocation, and colitogenic Th17 responses in mice

Oscar Medina-Contreras et al. J Clin Invest. 2011 Dec.

Abstract (V体育平台登录)

The two most common forms of inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis, affect approximately 1 million people in the United States. Uncontrolled APC reactivity toward commensal bacteria is implicated in the pathogenesis of the disease. A number of functionally distinct APC populations exist in the mucosal lamina propria (LP) below the intestinal epithelium, but their relative contributions to inflammation remain unclear. Here, we demonstrate in mice important roles for the chemokine receptor CX3CR1 in maintaining LP macrophage populations, preventing translocation of commensal bacteria to mesenteric lymph nodes (mLNs), and limiting colitogenic Th17 responses. CX3CR1 was found to be expressed in resident LP macrophages (defined as CD11b(+)F4/80(+)) but not DCs (defined as CD11c(+)CD103(+)). LP macrophage frequency and number were decreased in two strains of CX3CR1-knockout mice and in mice deficient in the CX3CR1 ligand CX3CL1. All these knockout strains displayed markedly increased translocation of commensal bacteria to mLNs. Additionally, the severity of DSS-induced colitis was dramatically enhanced in the knockout mice as compared with controls. Disease severity could be limited by either administration of neutralizing IL-17A antibodies or transfer of CX3CR1-sufficient macrophages VSports手机版. Our data thus suggest key roles for the CX3CR1/CX3CL1 axis in the intestinal mucosa; further clarification of CX3CR1 function will likely direct efforts toward therapeutic intervention for mucosal inflammatory disorders such as IBD. .

PubMed Disclaimer

Figures

Figure 1
Figure 1. Murine intestinal LP macrophages express CX3CR1.
(A) Flow cytometry of small (SI) and large (LI) intestine LP cells from C57BL/6 mice, stained for CD45, I-Ab, CD11b, CD11c, F4/80, and CD103. Populations were defined as R1, CD11b– DCs; R3, CD11c– macrophages; R4, CD11b+ DCs; and R5, CD11c+ macrophages. (B) GFP expression in LP macrophages (MΦ; solid histograms) and DCs (open histograms) in the small and large intestine of Cx3cr1gfp/gfp mice, assessed by flow cytometry and gated as in A. (C) qRT-PCR for Cx3cr1 mRNA expression in isolated intestinal LP APCs from Cx3cr1+/+ mice. Data are representative of 3 (B and C) or more than 3 (A) independent experiments. Error bars represent SD. *P < 0.05 versus respective controls.
Figure 2
Figure 2. Cx3cr1gfp/gfp mice harbor a specific reduction in LP macrophages.
(A) Percentage of CD45+MHC II+ macrophages and DCs in the small and large intestine of Cx3cr1gfp/gfp or Cx3cr1+/+ mice. (B) Total cellularity of CD45+MHC II+ macrophages and DCs in the small and large intestine of Cx3cr1gfp/gfp or Cx3cr1+/+ mice. (C) Percentage of bone marrow MDPs and blood monocytes of Cx3cr1gfp/gfp or Cx3cr1+/+ mice. Data are representative of 3 (C) or more than 3 (A and B) independent experiments. Error bars represent SEM. *P < 0.05 versus respective controls.
Figure 3
Figure 3. CX3CR1-deficient mice have increased bacterial translocation.
CFU per mouse in the mLNs of Cx3cr1gfp/gfp (A) and Cx3cr1–/– (B) mice. Relative abundance of phyla (C) and genera (D) among the translocated bacteria. Data are representative of 3 independent experiments, with 4 mice per group per experiment. *P < 0.05 versus respective controls.
Figure 4
Figure 4. Increased susceptibility to DSS-induced colitis in CX3CR1-deficient mice.
(A) Severity of colitis in DSS-treated Cx3cr1gfp/gfp and Cx3cr1–/– mice or their respective Cx3cr1+/+ age- and vendor-matched control mice, as measured by stool consistency, presence of fecal blood, and weight loss. (B) Colon histology of DSS-treated Cx3cr1gfp/gfp, Cx3cr1–/–, and Cx3cr1+/+ mice. Original magnification, ×400. Data are representative of 3 independent experiments. Error bars represent SEM. *P < 0.05.
Figure 5
Figure 5. IL-17 responses contribute to enhanced colitis in Cx3cr1gfp/gfp mice.
(A) Flow cytometry of intracellular Foxp3 or IL-17A by colonic CD4+ T cells from Cx3cr1gfp/gfp or Cx3cr1+/+ mice. Numbers in outlined areas indicate percentage of cells in gate. (B) Percentage of IL-17A+ and FoxP3+ cells in the large intestine of Cx3cr1gfp/gfp and Cx3cr1+/+ mice. (C) Severity of colitis in DSS-treated Cx3cr1gfp/gfp or Cx3cr1+/+ mice, in the presence of neutralizing IL-17A antibody or isotype control. Data are representative of 2 (C) or 3 (A and B) independent experiments. Error bars represent SEM. *P < 0.05 versus respective controls.
Figure 6
Figure 6. LP macrophage deficiency contributes to enhanced colitis in Cx3cr1gfp/gfp mice.
Severity of colitis in DSS-treated Cx3cr1gfp/gfp mice after adoptive transfer of Cx3cr1gfp/gfp or Cx3cr1+/+ BMDMs. Data are representative of 2 independent experiments. Error bars represent SEM. *P < 0.05 versus respective controls.
See this image and copyright information in PMC

References

    1. Janeway CA, Jr, Medzhitov R. Innate immune recognition. Annu Rev Immunol. 2002;20:197–216. doi: 10.1146/annurev.immunol.20.083001.084359. - DOI - PubMed
    1. Duchmann R, Kaiser I, Hermann E, Mayet W, Ewe K, Meyer zum Buschenfelde KH. Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease (IBD). Clin Exp Immunol. 1995;102(3):448–455. doi: 10.1111/j.1365-2249.1995.tb03836.x. - DOI - PMC - PubMed
    1. Izcue A, Coombes JL, Powrie F. Regulatory lymphocytes and intestinal inflammation. Annu Rev Immunol. 2009;27:313–338. doi: 10.1146/annurev.immunol.021908.132657. - DOI - PubMed
    1. Macdonald TT, Monteleone I, Fantini MC, Monteleone G. Regulation of homeostasis and inflammation in the intestine. Gastroenterology. 2011;140(6):1768–1775. doi: 10.1053/j.gastro.2011.02.047. - "V体育官网" DOI - PubMed
    1. Abraham C, Medzhitov R. Interactions between the host innate immune system and microbes in inflammatory bowel disease. Gastroenterology. 2011;140(6):1729–1737. - PMC - PubMed

"V体育平台登录" Publication types

MeSH terms

Substances