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Department of Pathology, University of Michigan, Ann Arbor, MI 48109
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-
B 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants HL74024, HL31237, and HL35276 (to S.L.K.).
2 Address correspondence and reprint requests to Dr. Steven L. Kunkel, University of Michigan, 109 Zina Pitcher Place, Biomedical Sciences Research Building, Room 4698, Ann Arbor, MI 48109-2200. E-mail address: slkunkel{at}med.umich.edu
3 Abbreviations used in this paper: aaM
, alternatively activated macrophage; ALT, alanine transaminase; AST, aspartate transaminase; FIZZ1, found in inflammatory zone 1; IRAK1, IL-1R associated kinase 1; Pam3Cys, Pam3Cys-Ser-(Lys)4; TAM, tumor-associated macrophage; TRAF6, TNFR-associated factor 6; WT, wild type.
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