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Chemokine receptor CCR8 is required for lipopolysaccharide-triggered cytokine production in mouse peritoneal macrophages.

ABSTRACT: Chemokine (C-C motif) receptor 8 (CCR8), the chemokine receptor for chemokine (C-C motif) ligand 1 (CCL1), is expressed in T-helper type-2 lymphocytes and peritoneal macrophages (PM?) and is involved in various pathological conditions, including peritoneal adhesions. However, the role of CCR8 in inflammatory responses is not fully elucidated. To investigate the function of CCR8 in macrophages, we compared cytokine secretion from mouse PM? or bone marrow-derived macrophages (BMM?) stimulated with various Toll-like receptor (TLR) ligands in CCR8 deficient (CCR8-/-) and wild-type (WT) mice. We found that CCR8-/- PM? demonstrated attenuated secretion of tumor necrosis factor (TNF)-?, interleukin (IL)-6, and IL-10 when stimulated with lipopolysaccharide (LPS). In particular, LPS-induced IL-10 production absolutely required CCR8. CCR8-dependent cytokine secretion was characteristic of PM? but not BMM?. To further investigate this result, we selected the small molecule compound R243 from a library of compounds with CCR8-antagonistic effects on CCL1-induced Ca2+ flux and CCL1-driven PM? aggregation. Similar to CCR8-/- PM?, R243 attenuated secretion of TNF-?, IL-6, and most strikingly IL-10 from WT PM?, but not BMM?. CCR8-/- PM? and R243-treated WT PM? both showed suppressed c-jun N-terminal kinase activity and nuclear factor-?B signaling after LPS treatment when compared with WT PM?. A c-Jun signaling pathway inhibitor also produced an inhibitory effect on LPS-induced cytokine secretion that was similar to that of CCR8 deficiency or R243 treatment. As seen in CCR8-/- mice, administration of R243 attenuated peritoneal adhesions in vivo. R243 also prevented hapten-induced colitis. These results are indicative of cross talk between signaling pathways downstream of CCR8 and TLR-4 that induces cytokine production by PM?. Through use of CCR8-/- mice and the new CCR8 inhibitor, R243, we identified a novel macrophage innate immune response pathway that involves a chemokine receptor.

SUBMITTER: Oshio T

PROVIDER: S-EPMC3979852 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Chemokine receptor CCR8 is required for lipopolysaccharide-triggered cytokine production in mouse peritoneal macrophages.

Oshio Tomoyuki T Kawashima Rei R Kawamura Yuki I YI Hagiwara Teruki T Mizutani Noriko N Okada Toshihiko T Otsubo Takeshi T Inagaki-Ohara Kyoko K Matsukawa Akihiro A Haga Tatsuya T Kakuta Shigeru S Iwakura Yoichiro Y Hosokawa Seijiro S Dohi Taeko T

PloS one 20140408 4

Chemokine (C-C motif) receptor 8 (CCR8), the chemokine receptor for chemokine (C-C motif) ligand 1 (CCL1), is expressed in T-helper type-2 lymphocytes and peritoneal macrophages (PMφ) and is involved in various pathological conditions, including peritoneal adhesions. However, the role of CCR8 in inflammatory responses is not fully elucidated. To investigate the function of CCR8 in macrophages, we compared cytokine secretion from mouse PMφ or bone marrow-derived macrophages (BMMφ) stimulated with ...[more]

PMID: 24714157

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Project description:Telocytes (TCs), a distinct interstitial cell population, have been identified in the uterus, oviduct and placenta, with multiple proposed potential biological functions. Their unique structure allows them to form intercellular junctions with various immunocytes, both in normal and diseased tissues, suggesting a potential functional relationship with the local immune response. It has been hypothesized that through direct heterocellular junctions or indirect paracrine effects, TCs influence the activity of local immunocytes that are involved in the inflammatory process and in immune-mediated reproductive abnormalities. However, no reliable cytological evidence for this hypothesis is currently available. In this study, we cultured primary murine uterine TCs and collected TC conditioned media (TCM). Mouse peritoneal macrophages (pMACs) were co-cultured for 48 hrs with TCM or with DMEM/F12 or lipopolysaccharide (LPS) as negative and positive controls, respectively. Normal uterine TCs with a typical structure and a CD-34-positive/vimentin-positive/c-kit-negative immunophenotype were observed during culture. Morphologically, TCM-treated pMACs displayed an obvious activation/immunoresponse, in contrast to over-stimulation and cell death after LPS treatment and no sign of activation in the presence of DMEM/F12. Accordingly, a cell counting kit 8 (CCK-8) assay indicated significant activation of pMACs by TCM and LPS compared to DMEM/F12, thus supporting the marked morphological differences among these groups of cells. Furthermore, within a panel of macrophage-derived cytokines/enzymes, interleukin-6 (IL-6) and inducible nitric oxide synthase were significantly elevated in TCM-treated pMACs; tumour necrosis factor α, IL1-R1, and IL-10 were slightly, but significantly, up-regulated; and no changes were observed for transforming growth factor-β1, IL-1β, IL-23α and IL-18. Our results indicate that TCs are not simply innocent bystanders but are rather functional players in the activation of pMACs; they trigger and maintain the immune response, likely through indirect paracrine effects. Thus, we provide preliminary in vitro evidence of immunoregulatory and immunosurveillance roles for TCs.

Dataset Information

Chemokine receptor CCR8 is required for lipopolysaccharide-triggered cytokine production in mouse peritoneal macrophages.

Publications

Chemokine receptor CCR8 is required for lipopolysaccharide-triggered cytokine production in mouse peritoneal macrophages.

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