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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 (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 various Toll-like receptor (TLR) ligands in CCR8 deficient (CCR8- /-) and wild-type (WT) mice. We found that CCR8-/- PMφ demonstrated attenuated secretion of tumor necrosis factor (TNF)-α, 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 PMφ but not BMMφ. 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 PMφ aggregation. Similar to CCR8-/- PMφ, R243 attenuated secretion of TNF-α, IL-6, and most strikingly IL-10 from WT PMφ, but not BMMφ. CCR8-/- PMφ and R243-treated WT PMφ both showed suppressed c-jun N-terminal kinase activity and nuclear factor-κB signaling after LPS treatment when compared with WT PMφ. 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 PMφ. 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.
Highlights
Chemokines are small proteins with a molecular mass of 6– 14 kDa that induce chemotaxis by binding to G-protein-coupled receptors (GPCRs) on the cell surface [1,2]
Based on our previous result that CCL1/CCR8 is involved in the innate immune responses in the peritoneal cavity [14], we examined the effect of CCR8 deficiency in macrophage responses to various Toll-like receptor (TLR) ligands
We found that LPS-induced tumor necrosis factor (TNF)-a and IL-6 production, but not other TLR ligands, was clearly attenuated in CCR8-/- PMQto levels less than 50% of that in WT PMQ
Summary
Chemokines are small proteins with a molecular mass of 6– 14 kDa that induce chemotaxis by binding to G-protein-coupled receptors (GPCRs) on the cell surface [1,2]. In a mouse model of ovalbumin (OVA)induced atopic dermatitis, CCL8 was shown to be highly expressed in the skin, where it induces the migration of a population of CCR8-positive IL-5-enriched Th2 cells into the skin, thereby driving eosinophilic inflammation. In addition to these reports of CCR8-positive T cells, CCR8-expressing macrophages play significant roles in several pathological situations. In vitro stimulation of the PMQ with CCL1 on mesothelial cell layer leads to macrophage aggregation In mice, such CCR8-positive macrophage aggregates are seen in vivo at the serosal sites of peritoneal adhesions induced by acute colitis or surgical manipulation of the peritoneal cavity. Attempts to identify pharmacological antagonists of CCR8 have been made [18,19,20]
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