title: CCR4 is a key modulator of innate immune responses.
abstract: CCR4 is recognized as a key receptor in Th2-associated immune processes, although very little is known about its role in innate immunity. Previous studies reported increased resistance to LPS-induced lethality in CCR4(-/-) mice compared with wild-type mice. This study demonstrates that CCR4(-/-) mice are similarly resistant to challenge with other TLR agonists, as well as bacterial peritonitis. Resistance was associated with enhanced early leukocyte recruitment, increased TLR expression, a skewed type 2 cytokine/chemokine profile, and improved bacterial clearance. Macrophages from CCR4(-/-) mice exhibited many features consistent with alternative activation, including elevated secretion of type 2 cytokines/chemokines and the found in inflammatory zone 1 (FIZZ1) protein. MyD88-dependent NF-kappaB signaling was significantly down-regulated in CCR4(-/-) macrophages, whereas p38 MAPK and JNK activation were conversely increased. These data stress the importance of CCR4 in macrophage differentiation and innate immune responses to pathogens, as well as the involvement of chemokine receptor expression in TLR signaling regulation.
authors.affiliation: Department of Pathology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA.
authors.forename: Traci L
authors.initials: TL
authors.lastname: Ness
authors.forename: Jillian L
authors.initials: JL
authors.lastname: Ewing
authors.forename: Cory M
authors.initials: CM
authors.lastname: Hogaboam
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
mesh_terms: D000818:Animals; D001424:Bacterial Infections / Q000276:immunology; D002454:Cell Differentiation; D002465:Cell Movement; D018925:Chemokines / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D007113:Immunity, Innate; D008070:Lipopolysaccharides / Q000276:immunology; D048670:MAP Kinase Kinase 4 / Q000276:immunology / Q000378:metabolism; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D010538:Peritonitis / Q000276:immunology; D054398:Receptors, CCR4; D019707:Receptors, Chemokine / Q000172:deficiency / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism
chemical_list: C515355:Ccr4 protein, mouse; D018925:Chemokines; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D054398:Receptors, CCR4; D019707:Receptors, Chemokine; D051193:Toll-Like Receptors; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4