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1.
A role for CCR9 in T lymphocyte development and migration 总被引:14,自引:0,他引:14
Uehara S Grinberg A Farber JM Love PE 《Journal of immunology (Baltimore, Md. : 1950)》2002,168(6):2811-2819
CCR9 mediates chemotaxis in response to CCL25/thymus-expressed chemokine and is selectively expressed on T cells in the thymus and small intestine. To investigate the role of CCR9 in T cell development, the CCR9 gene was disrupted by homologous recombination. B cell development, thymic alphabeta-T cell development, and thymocyte selection appeared unimpaired in adult CCR9-deficient (CCR9(-/-)) mice. However, competitive transplantation experiments revealed that bone marrow from CCR9(-/-) mice was less efficient at repopulating the thymus of lethally irradiated Rag-1(-/-) mice than bone marrow from littermate CCR9(+/+) mice. CCR9(-/-) mice had increased numbers of peripheral gammadelta-T cells but reduced numbers of gammadeltaTCR(+) and CD8alphabeta(+)alphabetaTCR(+) intraepithelial lymphocytes in the small intestine. Thus, CCR9 plays an important, although not indispensable, role in regulating the development and/or migration of both alphabeta(-) and gammadelta(-) T lymphocytes. 相似文献
2.
Shoji Uehara Kaimei Song Joshua M Farber Paul E Love 《Journal of immunology (Baltimore, Md. : 1950)》2002,168(1):134-142
CCR9 mediates chemotaxis of thymocytes in response to CCL25/thymus-expressed chemokine, and its mRNA is selectively expressed in thymus and small intestine, the two known sites of T lymphopoiesis. To examine the expression of CCR9 during lymphocyte development, we generated polyclonal Ab that recognizes murine CCR9. CCR9 was expressed on the majority of immature CD4+CD8+ (double-positive) thymocytes, but not on immature CD4(-)CD8(-) (double-negative) thymocytes. CCR9 was down-regulated during the transition of double-positive thymocytes to the CD4+ or CD8+ (single-positive) stage, and only a minor subset of CD8+ lymph node T cells expressed CCR9. All CCR9+ thymocyte subsets migrated in response to CCL25; however, CD69+ thymocytes demonstrated enhanced CCL25-induced migration compared with CD69(-) thymocytes. Ab-mediated TCR stimulation also enhanced CCL25 responsiveness, indicating that CCL25-induced thymocyte migration is augmented by TCR signaling. Approximately one-half of all gammadeltaTCR+ thymocytes and peripheral gammadeltaTCR+ T cells expressed CCR9 on their surface, and these cells migrated in response to CCL25. These findings suggest that CCR9 may play an important role in the development and trafficking of both alphabetaTCR+ and gammadeltaTCR+ T cells. 相似文献
3.
4.
Differential role of CCR2 in islet and heart allograft rejection: tissue specificity of chemokine/chemokine receptor function in vivo 总被引:5,自引:0,他引:5
Abdi R Means TK Ito T Smith RN Najafian N Jurewicz M Tchipachvili V Charo I Auchincloss H Sayegh MH Luster AD 《Journal of immunology (Baltimore, Md. : 1950)》2004,172(2):767-775
Chemokines have a pivotal role in the mobilization and activation of specific leukocyte subsets in acute allograft rejection. However, the role of specific chemokines and chemokine receptors in islet allograft rejection has not been fully elucidated. We now show that islet allograft rejection is associated with a steady increase in intragraft expression of the chemokines CCL8 (monocyte chemoattractant protein-2), CCL9 (monocyte chemoattractant protein-5), CCL5 (RANTES), CXCL-10 (IFN-gamma-inducible protein-10), and CXCL9 (monokine induced by IFN-gamma) and their corresponding chemokine receptors CCR2, CCR5, CCR1, and CXCR3. Because CCR2 was found to be highly induced, we tested the specific role of CCR2 in islet allograft rejection by transplanting fully MHC mismatched islets from BALB/c mice into C57BL/6 wild-type (WT) and CCR2-deficient mice (CCR2-/-). A significant prolongation of islet allograft survival was noted in CCR2-/- recipients, with median survival time of 24 and 12 days for CCR2-/- and WT recipients, respectively (p < 0.0001). This was associated with reduction in the generation of CD8+, but not CD4+ effector alloreactive T cells (CD62L(low)CD44(high)) in CCR2-/- compared with WT recipients. In addition, CCR2-/- recipients had a reduced Th1 and increased Th2 alloresponse in the periphery (by ELISPOT analysis) as well as in the grafts (by RT-PCR). However, these changes were only transient in CCR2-/- recipients that ultimately rejected their grafts. Furthermore, in contrast to the islet transplants, CCR2 deficiency offered only marginal prolongation of heart allograft survival. This study demonstrates the important role for CCR2 in early islet allograft rejection and highlights the tissue specificity of the chemokine/chemokine receptor system in vivo in regulating allograft rejection. 相似文献
5.
ML Quick S Mukherjee CN Rudick JD Done AJ Schaeffer P Thumbikat 《American journal of physiology. Regulatory, integrative and comparative physiology》2012,303(6):R580-R589
Experimental autoimmune prostatitis (EAP) is a murine model of chronic prostatitis/chronic pelvic pain syndrome (CPPS) in men, a syndrome characterized by chronic pelvic pain. We have demonstrated that chemokine ligands CCL2 and CCL3 are biomarkers that correlate with pelvic pain symptoms. We postulated that CCL2 and CCL3 play a functional role in CPPS and therefore examined their expression in EAP. Upon examination of the prostate 5 days after induction of EAP, CCL2 mRNA was elevated 2- to 3-fold, CCL8 by 15-fold, CCL12 by 12- to 13-fold, and CXCL9 by 2- to 4-fold compared with control mice. At 10 days the major chemokines were CXCL13 and CXCL2; at 20 days CCL2 (1- to 2-fold), CCL3 (2- to 3-fold) and CCL11 (2- to 3-fold); and at 30 days, CCL12 (20- to 35-fold) and smaller increases in CCL2, CCL3, and XCL1. Chemokine elevations were accompanied by increases in mast cells and B cells at 5 days, monocytes and neutrophils at day 10, CD4+ T cells at day 20, and CD4+ and CD8+ T cells at day 30. Anti-CCL2 and anti-CCL3 neutralizing antibodies administered at EAP onset attenuated pelvic pain development, but only anti-CCL2 antibodies were effective therapeutically. CCL2- and its cognate receptor CCR2-deficient mice were completely protected from development of pain symptoms but assumed susceptibility after reconstitution with wild-type bone marrow. CCL3-deficient mice showed resistance to the maintenance of pelvic pain while CCR5-deficient mice did not show any lessening of pelvic pain severity. These results suggest that the CCL2-CCR2 axis and CCL3 are important mediators of chronic pelvic pain in EAP. 相似文献
6.
Chemokines and their receptors fulfill specialized roles in inflammation and under homeostatic conditions. CCR7 and its ligands, CCL19 and CCL21, are involved in lymphocyte recirculation through secondary lymphoid organs and additionally navigate lymphocytes into distinct tissue compartments. The role of CCR7 in the migration of polarized T effector/memory cell subsets in vivo is still poorly understood. We therefore analyzed murine and human CD4(+) cytokine-producing cells developed in vivo for their chemotactic reactivity to CCR7 ligands. The responses of cells producing cytokines, such as IFN-gamma, IL-4, and IL-10, as well as of subsets defined by memory or activation markers were comparable to that of naive CD4(+) cells, with slightly lower reactivity in cells expressing IL-10 or CD69. This indicates that CCR7 ligands are able to attract naive as well as the vast majority of activated and effector/memory T cell stages. Chemotactic reactivity of these cells toward CCL21 was absent in CCR7-deficient cells, proving that effector cells do not use alternative receptors for this chemokine. Th1 cells generated from CCR7(-/-) mice failed to enter lymph nodes and Peyer's patches, but did enter a site of inflammation. These findings indicate that CD4(+) cells producing effector cytokines upon stimulation retain the capacity to recirculate through lymphoid tissues via CCR7. 相似文献
7.
Susceptibility of CCR5-deficient mice to genital herpes simplex virus type 2 is linked to NK cell mobilization
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Following genital herpes simplex virus type 2 (HSV-2) exposure, NK cells and T cells are mobilized to sites of infection to control viral replication and spread. The present investigation sought to determine the role of the chemokine receptor CCR5 in this process. Mice deficient in CCR5 (CCR5-/-) displayed a significant reduction in cumulative survival following infection in comparison to wild-type, HSV-2-infected controls. Associated with decreased resistance to viral infection, CCR5-/- mice yielded significantly more virus and expressed higher levels of tumor necrosis factor alpha, CXCL1, CCL2, CCL3, and CCL5 in the vagina, spinal cord, and/or brain stem than did wild-type mice. Whereas there was no difference in absolute number of leukocytes (CD45high), CD4 T cells, or CD8 T cells residing in the draining lymph nodes, spleen, spinal cord, or brain stem comparing HSV-2-infected wild-type to CCR5-/- mice prior to or after infection, there were significantly more NK cells (NK1.1+ CD3-) residing in the brain stem and spleen of infected wild-type mice. Functionally, NK activity from cells isolated from the brain stem of HSV-2-infected wild-type mice was greater than that from HSV-2-infected CCR5-/- mice. In addition, antibody-mediated depletion of NK cells resulted in an increase in HSV-2 levels in the vaginal, spinal cord, and brain stem tissue of wild-type but not CCR5-/- mice. Collectively, the absence of CCR5 expression significantly impacts the ability of the host to control genital HSV-2 infection, inflammation, and spread associated with a specific reduction in NK cell expansion, infiltration, and activity in the nervous system. 相似文献
8.
CCL9 is secreted by the follicle-associated epithelium and recruits dome region Peyer's patch CD11b+ dendritic cells 总被引:8,自引:0,他引:8
Zhao X Sato A Dela Cruz CS Linehan M Luegering A Kucharzik T Shirakawa AK Marquez G Farber JM Williams I Iwasaki A 《Journal of immunology (Baltimore, Md. : 1950)》2003,171(6):2797-2803
The follicle-associated epithelium (FAE) secretes chemokines important in the recruitment of various cell types including CCL20 (MIP-3alpha). CCL20 is chemotactic to the CD11b(+) dendritic cells (DCs) distributed in the subepithelial dome regions of the Peyer's patches, and mice deficient in the receptor for CCL20, CCR6, have been reported to be devoid of the CD11b(+) DCs in the dome regions. Here, we describe another chemokine specifically secreted from the FAE of mouse Peyer's patches, CCL9 (MIP-1gamma, CCF18, MRP-2). By in situ hybridization, we demonstrated that CCL9 mRNA was expressed by the FAE but not by the villus epithelium. At the protein level, CCL9 was detected on the FAE and on extracellular matrix structures within the dome regions of the Peyer's patches. By RT-PCR, we demonstrated that one of the putative receptors for CCL9, CCR1, was expressed by the Peyer's patch CD11b(+) DCs and in a chemotaxis assay, CD11b(+) DCs migrated toward CCL9. To compare the abilities of the chemokines CCL20 and CCL9 to recruit CD11b(+) DCs to the dome regions, we examined the in vivo distribution of these cells in CCR6-deficient, CCL9-blocked wild type, or CCL9-blocked CCR6-deficient mice. To our surprise, using a sensitive immunofluorescence analysis, we observed that CD11b(+) DCs were present in the dome regions of the CCR6-deficient mice. In contrast, Ab neutralization of CCL9 in vivo resulted in significant reduction of the CD11b(+) DC number in the subepithelial dome regions of Peyer's patches of both wild type and CCR6 -/- mice. Taken together, these results demonstrate an important role of CCL9 in CD11b(+) DC recruitment to the dome regions of mouse Peyer's patches. 相似文献
9.
Naive T cell recruitment to nonlymphoid tissues: a role for endothelium-expressed CC chemokine ligand 21 in autoimmune disease and lymphoid neogenesis 总被引:13,自引:0,他引:13
Weninger W Carlsen HS Goodarzi M Moazed F Crowley MA Baekkevold ES Cavanagh LL von Andrian UH 《Journal of immunology (Baltimore, Md. : 1950)》2003,170(9):4638-4648
Naive T cells are usually excluded from nonlymphoid tissues. Only when such tertiary tissues are subjected to chronic inflammation, such as in some (but not all) autoimmune diseases, are naive T cells recruited to these sites. We show that the CCR7 ligand CC chemokine ligand (CCL)21 is sufficient for attracting naive T cells into tertiary organs. We performed intravital microscopy of cremaster muscle venules in T-GFP mice, in which naive T cells express green fluorescent protein (GFP). GFP(+) cells underwent selectin-dependent rolling, but no firm adherence (sticking). Superfusion with CCL21, but not CXC chemokine ligand 12, induced integrin-dependent sticking of GFP(+) cells. Moreover, CCL21 rapidly elicited accumulation of naive T cells into sterile s.c. air pouches. Interestingly, a second CCR7 ligand, CCL19, triggered T cell sticking in cremaster muscle venules, but failed to induce extravasation in air pouches. Immunohistochemistry studies implicate ectopic expression of CCL21 as a mechanism for naive T cell traffic in human autoimmune diseases. Most blood vessels in tissue samples from patients with rheumatoid arthritis (85 +/- 10%) and ulcerative colitis (66 +/- 1%) expressed CCL21, and many perivascular CD45RA(+) naive T cells were found in these tissues, but not in psoriasis, where CCL21(+) vessels were rare (17 +/- 1%). These results identify endothelial CCL21 expression as an important determinant for naive T cell migration to tertiary tissues, and suggest the CCL21/CCR7 pathway as a therapeutic target in diseases that are associated with naive T cell recruitment. 相似文献
10.
Yu CR Peden KW Zaitseva MB Golding H Farber JM 《Journal of immunology (Baltimore, Md. : 1950)》2000,164(3):1293-1305
We isolated cDNAs for a chemokine receptor-related protein having the database designation GPR-9-6. Two classes of cDNAs were identified from mRNAs that arose by alternative splicing and that encode receptors that we refer to as CCR9A and CCR9B. CCR9A is predicted to contain 12 additional amino acids at its N terminus as compared with CCR9B. Cells transfected with cDNAs for CCR9A and CCR9B responded to the chemokine CC chemokine ligand 25 (CCL25)/thymus-expressed chemokine (TECK)/chemokine beta-15 (CK beta-15) in assays for both calcium flux and chemotaxis. No other chemokines tested produced responses specific for the cDNA-transfected cells. mRNA for CCR9A/B is expressed predominantly in the thymus, coincident with the expression of CCL25, and highest expression for CCR9A/B among thymocyte subsets was found in CD4+CD8+ cells. mRNAs encoding the A and B forms of the receptor were expressed at a ratio of approximately 10:1 in immortalized T cell lines, in PBMC, and in diverse populations of thymocytes. The EC50 of CCL25 for CCR9A was lower than that for CCR9B, and CCR9A was desensitized by doses of CCL25 that failed to silence CCR9B. CCR9 is the first example of a chemokine receptor in which alternative mRNA splicing leads to proteins of differing activities, providing a mechanism for extending the range of concentrations over which a cell can respond to increments in the concentration of ligand. The study of CCR9A and CCR9B should enhance our understanding of the role of the chemokine system in T cell biology, particularly during the stages of thymocyte development. 相似文献
11.
Freeman CM Chiu BC Stolberg VR Hu J Zeibecoglou K Lukacs NW Lira SA Kunkel SL Chensue SW 《Journal of immunology (Baltimore, Md. : 1950)》2005,174(4):1962-1970
CCR8 was initially described as a Th2 cell-restricted receptor, but this has not been fully tested in vivo. The present study used ex vivo and in vivo approaches to examine the distribution and functional significance of CCR8 among CD4+ T cells. Populations of cytokine-secreting CD4+ T cells were generated in primed mice with Th1 or Th2 cell-mediated pulmonary granulomas, respectively elicited by i.v. challenge with either Mycobacteria bovis purified protein derivative- or Schistosoma mansoni egg Ag (SEA)-coated beads. Cytokine-producing CD4+ T cells were isolated from Ag-stimulated draining lymph node cultures by positive selection. Quantitative analysis of cytokine mRNA indicated enriched populations of IFN-gamma-, IL-4-, and IL-10-producing cells. Analysis of chemokine receptor mRNA indicated that IL-10+ cells selectively expressed CCR8 in the SEA bead-elicited type 2 response. The IL-10+CCR8+ populations were CD25+ and CD44+ but lacked enhanced Foxp3 expression. Adoptive transfer to naive recipients indicated that IL-10+ T cells alone could not transfer type 2 inflammation. Analysis of SEA bead-challenged CCR8-/- mice indicated significantly impaired IL-10 production as well as reductions in granuloma eosinophils. Adoptive transfer of CD4+CCR8+/+ T cells corrected cytokine and inflammation defects, but the granuloma eosinophil recruitment defect persisted when donor cells were depleted of IL-10+ cells. Accordingly, local IL-10 production correlated with CCR8 ligand (CCL1) expression and the appearance of CCR8+ cells in granulomatous lungs. Thus, IL-10-producing, CCR8+CD4+CD25+CD44+ T cells are generated during SEA challenge, which augment the Th2-mediated eosinophil-rich response to the parasite Ags. 相似文献
12.
Sato K Kawasaki H Morimoto C Yamashima N Matsuyama T 《Journal of immunology (Baltimore, Md. : 1950)》2002,168(12):6263-6272
Human memory CD4(+) T cells respond better to inflammatory CCLs/CC chemokines, CCL3 and CCL5, than naive CD4(+) T cells. We analyzed the regulatory mechanism underlying this difference. Memory and naive CD4(+) T cells expressed similarly high levels of CCR1; however, CCR5 was only expressed in memory CD4(+) T cells at low levels. Experiments using mAbs to block chemokine receptors revealed that CCR1 functioned as a major receptor for the binding of CCL5 in memory and naive CD4(+) T cells as well as the ligand-induced chemotaxis in memory CD4(+) T cells. Stimulation of memory CD4(+) T cells with CCL5 activated protein tyrosine kinase-dependent cascades, which were significantly blocked by anti-CCR1 mAb, whereas this stimulation failed to induce these events in naive CD4(+) T cells. Intracellular expressions of regulator of G protein signaling 3 and 4 were only detected in naive CD4(+) T cells. Pretreatment of cell membrane fractions from memory and naive CD4(+) T cells with GTP-gamma S inhibited CCL5 binding, indicating the involvement of G proteins in the interaction of CCL5 and its receptor(s). In contrast, CCL5 enhanced the GTP binding to G(i alpha) and G(q alpha) in memory CD4(+) T cells, but not in naive CD4(+) T cells. Thus, a failure of the ligand-induced activation of CCR1-mediated downstream signaling event as well as a deficiency of CCR5 expression may be involved in the hyporesponsiveness of naive CD4(+) T cells to CCL3 and CCL5. 相似文献
13.
Turner JE Paust HJ Steinmetz OM Peters A Meyer-Schwesinger C Heymann F Helmchen U Fehr S Horuk R Wenzel U Kurts C Mittrücker HW Stahl RA Panzer U 《Journal of immunology (Baltimore, Md. : 1950)》2008,181(9):6546-6556
The chemokine receptor CCR5 is predominantly expressed on monocytes and Th1-polarized T cells, and plays an important role in T cell and monocyte recruitment in inflammatory diseases. To investigate the functional role of CCR5 in renal inflammation, we induced a T cell-dependent model of glomerulonephritis (nephrotoxic serum nephritis) in CCR5(-/-) mice. Induction of nephritis in wild-type mice resulted in up-regulation of renal mRNA expression of the three CCR5 chemokine ligands, CCL5 (15-fold), CCL3 (4.9-fold), and CCL4 (3.4-fold), in the autologous phase of the disease at day 10. The up-regulated chemokine expression was paralleled by infiltration of monocytes and T cells, followed by renal tissue injury, albuminuria, and loss of renal function. Nephritic CCR5(-/-) mice showed a 3- to 4-fold increased renal expression of CCL5 (61.6-fold vs controls) and CCL3 (14.1-fold vs controls), but not of CCL4, in comparison with nephritic wild-type mice, which was accompanied by augmented renal T cell and monocyte recruitment and increased lethality due to uremia. Furthermore, CCR5(-/-) mice showed an increased renal Th1 response, whereas their systemic humoral and cellular immune responses were unaltered. Because the CCR5 ligands CCL5 and CCL3 also act via CCR1, we investigated the effects of the pharmacological CCR1 antagonist BX471. CCR1 blockade in CCR5(-/-) mice significantly reduced renal chemokine expression, T cell infiltration, and glomerular crescent formation, indicating that increased renal leukocyte recruitment and consecutive tissue damage in nephritic CCR5(-/-) mice depended on functional CCR1. In conclusion, this study shows that CCR5 deficiency aggravates glomerulonephritis via enhanced CCL3/CCL5-CCR1-driven renal T cell recruitment. 相似文献
14.
Wu Y Li YY Matsushima K Baba T Mukaida N 《Journal of immunology (Baltimore, Md. : 1950)》2008,181(9):6384-6393
Metastasis proceeds through interaction between cancer cells and resident cells such as leukocytes and fibroblasts. An i.v. injection of a mouse renal cell carcinoma, Renca, into wild-type mice resulted in multiple metastasis foci in lungs and was associated with intratumoral accumulation of macrophages, granulocytes, and fibroblasts. A chemokine, CCL3, was detected in infiltrating cells and, to a lesser degree, tumor cells, together with an infiltration of leukocytes expressing CCR5, a specific receptor for CCL3. A deficiency of the CCL3 or CCR5 gene markedly reduced the number of metastasis foci in the lung, and the analysis using bone marrow chimeric mice revealed that both bone marrow- and non-bone marrow-derived cells contributed to metastasis formation. CCL3- and CCR5-deficient mice exhibited a reduction in intratumoral accumulation of macrophages, granulocytes, and fibroblasts. Moreover, intratumoral neovascularization, an indispensable process for metastasis, was attenuated in these gene-deficient mice. Intrapulmonary expression of matrix metalloproteinase (MMP)-9 and hepatocyte growth factor (HGF) was enhanced in wild-type mice, and the increases were markedly diminished in CCL3- and CCR5-deficient mice. Furthermore, MMP-9 protein was detected in macrophages and granulocytes, the cells that also express CCR5 and in vitro stimulation by CCL3-induced macrophages to express MMP-9. Intratumoral fibroblasts expressed CCR5 and HGF protein. In vitro CCL3 stimulated fibroblasts to express HGF. Collectively, the CCL3-CCR5 axis appears to regulate intratumoral trafficking of leukocytes and fibroblasts, as well as MMP-9 and HGF expression, and as a consequence to accelerate neovascularization and subsequent metastasis formation. 相似文献
15.
Noah J. Tubo Marc A. Wurbel Trevor T. Charvat Thomas J. Schall Matthew J. Walters James J. Campbell 《PloS one》2012,7(11)
A goal for developers of immunomodulatory drugs has long been a systemically administered small molecule that can selectively inhibit inflammation in specific tissues. The chemokine receptor CCR9 is an attractive target for this approach, as entry of T cells into the small intestine from blood requires interaction between CCR9 and its ligand CCL25. We have tested the ability of a small molecule CCR9 antagonist, CCX8037, to inhibit antigen-mediated T cell accumulation in the intestine. This compound prevented accumulation of gut-imprinted antigen-specific CD8 T cells within epithelium of the small intestine. Interestingly, the antagonist did not affect the robust generation of gut-imprinted CD8 T cells within mesenteric lymph nodes. To distinguish “gut-selective” from “general” T cell inhibition, we tested the drug’s ability to influence accumulation of T cells within skin, a tissue in which CCR9 plays no known role, and we found no appreciable effect. This study demonstrates the feasibility of creating systemically-administered pharmaceuticals capable of tissue-selective immune modulation. This proof of concept is of utmost importance for designing effective treatments against various autoimmune disorders localized to a specific tissue. 相似文献
16.
Coordinated involvement of mast cells and T cells in allergic mucosal inflammation: critical role of the CC chemokine ligand 1:CCR8 axis 总被引:2,自引:0,他引:2
Gonzalo JA Qiu Y Lora JM Al-Garawi A Villeval JL Boyce JA Martinez-A C Marquez G Goya I Hamid Q Fraser CC Picarella D Cote-Sierra J Hodge MR Gutierrez-Ramos JC Kolbeck R Coyle AJ 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(3):1740-1750
CCL1 is the predominant chemokine secreted from IgE-activated human and mouse mast cells in vitro, colocalizes to mast cells in lung biopsies, and is elevated in asthmatic airways. CCR8, the receptor for CCL1, is expressed by approximately 70% of CD4(+) T lymphocytes recruited to the asthmatic airways, and the number of CCR8-expressing cells is increased 3-fold in the airways of asthmatic subjects compared with normal volunteers. In vivo, CCL1 expression in the lung is reduced in mast cell-deficient mice after aeroallergen provocation. Neutralization of CCL1 or CCR8 deficiency results in reduced mucosal lung inflammation, airway hyperresponsiveness, and mucus hypersecretion to a similar degree as detected in mast cell-deficient mice. Adenoviral delivery of CCL1 to the lungs of mast cell-deficient mice restores airway hyperresponsiveness, lung inflammation, and mucus hypersecretion to the degree observed in wild-type mice. The consequences of CCR8 deficiency, including a marked reduction in Th2 cytokine levels, are comparable with those observed by depletion of CD4(+) T lymphocytes. Thus, mast cell-derived CCL1- and CCR8-expressing CD4(+) effector T lymphocytes play an essential role in orchestrating lung mucosal inflammatory responses. 相似文献
17.
Waka Yokoyama Hitoshi Kohsaka Kayoko Kaneko Matthew Walters Aiko Takayasu Shin Fukuda Chie Miyabe Yoshishige Miyabe Paul E Love Nobuhiro Nakamoto Takanori Kanai Kaori Watanabe-Imai Trevor T Charvat Mark ET Penfold Juan Jaen Thomas J Schall Masayoshi Harigai Nobuyuki Miyasaka Toshihiro Nanki 《Arthritis research & therapy》2014,16(5)
Introduction
Biological drugs are effective in patients with rheumatoid arthritis (RA), but increase severe infections. The CC chemokine receptor (CCR) 9 antagonist was effective for Crohn’s disease without critical adverse effects including infections in clinical trials. The present study was carried out to explore the pathogenic roles of chemokine (C-C motif) ligand (CCL) 25 and its receptor, CCR9, in autoimmune arthritis and to study if the CCR9 antagonist could be a new treatment for RA.Methods
CCL25 and CCR9 expression was examined with immunohistochemistry and Western blotting. Concentration of interleukin (IL)-6, matrix metalloproteinase (MMP)-3 and tumor necrosis factor (TNF)-α was measured with enzyme-linked immunosorbent assays. Effects of abrogating CCR9 on collagen-induced arthritis (CIA) was evaluated using CCR9-deficient mice or the CCR9 antagonist, CCX8037. Fluorescence labeled-CD11b+ splenocytes from CIA mice were transferred to recipient CIA mice and those infiltrating into the synovial tissues of the recipient mice were counted.Results
CCL25 and CCR9 proteins were found in the RA synovial tissues. CCR9 was expressed on macrophages, fibroblast-like synoviocytes (FLS) and dendritic cells in the synovial tissues. Stimulation with CCL25 increased IL-6 and MMP-3 production from RA FLS, and IL-6 and TNF-α production from peripheral blood monocytes. CIA was suppressed in CCR9-deficient mice. CCX8037 also inhibited CIA and the migration of transferred CD11b+ splenocytes into the synovial tissues.Conclusions
The interaction between CCL25 and CCR9 may play important roles in cell infiltration into the RA synovial tissues and inflammatory mediator production. Blocking CCL25 or CCR9 may represent a novel safe therapy for RA. 相似文献18.
Ness TL Carpenter KJ Ewing JL Gerard CJ Hogaboam CM Kunkel SL 《Journal of immunology (Baltimore, Md. : 1950)》2004,173(11):6938-6948
CCR1 has previously been shown to play important roles in leukocyte trafficking, pathogen clearance, and the type 1/type 2 cytokine balance, although very little is known about its role in the host response during sepsis. In a cecal ligation and puncture model of septic peritonitis, CCR1-deficient (CCR1(-/-)) mice were significantly protected from the lethal effects of sepsis when compared with wild-type (WT) controls. The peritoneal and systemic cytokine profile in CCR1(-/-) mice was characterized by a robust, but short-lived and regulated antibacterial response. CCR1 expression was not required for leukocyte recruitment, suggesting critical differences extant in the activation of WT and CCR1(-/-) resident or recruited peritoneal cells during sepsis. Peritoneal macrophages isolated from naive CCR1(-/-) mice clearly demonstrated enhanced cytokine/chemokine generation and antibacterial responses compared with similarly treated WT macrophages. CCR1 and CCL5 interactions markedly altered the inflammatory response in vivo and in vitro. Administration of CCL5 increased sepsis-induced lethality in WT mice, whereas neutralization of CCL5 improved survival. CCL5 acted in a CCR1-dependent manner to augment production of IFN-gamma and MIP-2 to damaging levels. These data illustrate that the interaction between CCR1 and CCL5 modulates the innate immune response during sepsis, and both represent potential targets for therapeutic intervention. 相似文献
19.
Homeostasis of T cell numbers in the periphery implies an ability of lymphocytes to sense cell numbers. Although the mechanisms are unknown, we find that the chemokine CCL21 (also known as TCA4, SLC, 6Ckine), a ligand for the chemokine receptor CCR7, can regulate homeostasis of CD4 (but not CD8) T cells. In the absence of CCR7 ligands, transferred CD4 T cells failed to expand in lymphopenic hosts, whereas in the presence of CCL21 overexpression, homeostatic CD4 T cell proliferation occurred even in nonlymphopenic recipients. Ag-specific CD4 T cells transferred into Ag-expressing mice proliferated and induced autoimmunity only in lymphopenic recipients. Pancreatic expression of CCL21 was sufficient to replace the requirement for lymphopenia in the progression of autoimmune disease. These results suggest that CD4 T cells use local concentrations of CCR7 ligands as an index of T cell steady state numbers and that homeostatic expansion of the T cell population may be a contributing factor in the development of autoimmune disease. 相似文献
20.
Seth S Oberdörfer L Hyde R Hoff K Thies V Worbs T Schmitz S Förster R 《Journal of immunology (Baltimore, Md. : 1950)》2011,186(6):3364-3372
The chemokine receptor CCR7 represents an important determinant for circulating lymphocytes to enter lymph nodes (LN) via high endothelial venules. High endothelial venules also represent the major site of entry for plasmacytoid dendritic cells (pDC). In the steady-state, murine pDC have been suggested to home to LN engaging the chemokine receptors CXCR3, CXCR4, and CCR5, whereas responsiveness to CCR7 ligands is thought to be acquired only upon activation. In this study, we show that already resting pDC express minute amounts of CCR7 that suffice to trigger migration to CCL19/CCL21 in vitro. Upon activation with TLR ligands, CCR7 levels on pDC are strongly increased. Notably, CCR7-deficient mice display substantially reduced pDC counts in LN but not in bone marrow and spleen. Adoptive cell transfer experiments revealed that under both steady-state as well as inflammatory conditions, the homing of CCR7-deficient pDC is severely impaired, indicating that the reduced cell counts of naive pDC observed in CCR7(-/-) mice reflect an intrinsic homing defect of pDC. Together, these observations provide strong evidence that similar to naive lymphocytes, nonstimulated pDC exploit CCR7 to gain entry into LN. This adds to the repertoire of chemokine receptors permitting them to enter diverse tissues. 相似文献