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Chemokine receptor CCR8 is required for lipopolysaccharide-triggered cytokine production in mouse peritoneal macrophages.
- Source :
-
PloS one [PLoS One] 2014 Apr 08; Vol. 9 (4), pp. e94445. Date of Electronic Publication: 2014 Apr 08 (Print Publication: 2014). - Publication Year :
- 2014
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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.
- Subjects :
- Animals
Chemokine CCL1 antagonists & inhibitors
Chemotaxis drug effects
Chemotaxis immunology
Colitis genetics
Colitis immunology
Colitis metabolism
Disease Models, Animal
Inflammation genetics
Inflammation immunology
Inflammation metabolism
Intracellular Space metabolism
Lipopolysaccharides immunology
Macrophages drug effects
Macrophages immunology
Macrophages metabolism
Macrophages, Peritoneal drug effects
Macrophages, Peritoneal immunology
Male
Mice
Mice, Knockout
Protein Transport
Receptors, CCR8 antagonists & inhibitors
Receptors, CCR8 deficiency
Receptors, CCR8 genetics
Signal Transduction drug effects
Toll-Like Receptors metabolism
Cytokines biosynthesis
Macrophages, Peritoneal metabolism
Receptors, CCR8 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 9
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 24714157
- Full Text :
- https://doi.org/10.1371/journal.pone.0094445