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* Department of Forensic Medicine and
Department of Microbiology, Wakayama Medical University, Wakayama, Japan; and
Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
Cecal ligation and puncture (CLP) caused septic peritonitis in wild-type (WT) mice, with 
33% mortality within 7 days after the procedure. Concomitantly, the protein level of intraperitoneal CX3CL1/fractalkine was increased, with infiltration by CX3CR1-expressing macrophages into the peritoneum. CLP induced 75% mortality in CX3CR1-deficient (CX3CR1–/–) mice, which, however, exhibited a similar degree of intraperitoneal leukocyte infiltration as WT mice. Despite this, CX3CR1–/– mice exhibited impairment in intraperitoneal bacterial clearance, together with a reduction in the expression of intraperitoneal inducible NO synthase (iNOS) and bactericidal proinflammatory cytokines, including IL-1β, TNF-
, IFN-
, and IL-12, compared with WT mice. Bactericidal ability of peritoneal phagocytes such as neutrophils and macrophages was consistently attenuated in CX3CR1–/– mice compared with WT mice. Moreover, when WT macrophages were stimulated in vitro with CX3CL1, their bactericidal activity was augmented in a dose-dependent manner, with enhanced iNOS gene expression and subsequent NO generation. Furthermore, CX3CL1 enhanced the gene expression of IL-1β, TNF-, IFN-, and IL-12 by WT macrophages with NF-
B activation. Thus, CX3CL1-CX3CR1 interaction is crucial for optimal host defense against bacterial infection by activating bacterial killing functions of phagocytes, and by augmenting iNOS-mediated NO generation and bactericidal proinflammatory cytokine production mainly through the NF-B signal pathway, with few effects on macrophage infiltration.
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 in part from Grants-in-Aid from the Ministry of Education, Culture, Science, and Technology of the Japanese Government. T.H. is a recipient of a Research Fellowship for Young Scientists from the Japanese Society for the Promotion of Science.
2 Y.I. and T.H. contributed equally to this work.
3 Current address: Department of Legal Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan.
4 Current address: Division of Anaerobe Research, Life Science Research Center, Gifu University, Gifu 501-1194, Japan.
5 Address correspondence and reprint requests to Dr. Toshikazu Kondo, Department of Forensic Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan. E-mail address: kondot{at}wakayama-med.ac.jp
6 Abbreviations used in this paper: CLP, cecal ligation and puncture; iNOS, inducible NO synthase; pAb, polyclonal Ab; WT, wild type; ALT, alanine transferarse; BUN, blood urea nitrogen; Cr, creatinine; TSA, trypticase soy agar.
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  Y. Luo, B. M. Isaac, A. Casadevall, and D. Cox Phagocytosis Inhibits F-Actin-Enriched Membrane Protrusions Stimulated by Fractalkine (CX3CL1) and Colony-Stimulating Factor 1 Infect. Immun., October 1, 2009; 77(10): 4487 - 4495. [Abstract] [Full Text] [PDF]
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