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Unformatted text preview: Essential Involvement of CX3CR1-Mediated Signals in the Bactericidal Host Defense during Septic Peritonitis 1 Yuko Ishida, 2 * Takahito Hayashi, 2,3 * Takatsugu Goto, 4† Akihiko Kimura,* Shigeru Akimoto, † Naofumi Mukaida, ‡ and Toshikazu Kondo 5 * 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 2 / 2 ) mice, which, however, exhibited a similar degree of intraperitoneal leukocyte infiltration as WT mice. Despite this, CX3CR1 2 / 2 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-1 b , TNF- a , IFN- g , and IL-12, compared with WT mice. Bactericidal ability of peritoneal phagocytes such as neutrophils and macrophages was consistently attenuated in CX3CR1 2 / 2 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-1 b , TNF- a , IFN- g , and IL-12 by WT macrophages with NF- k 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- k B signal pathway, with few effects on macrophage infiltration. The Journal of Immunology, 2008, 181: 4208–4218. S epsis is a severe systemic bacterial infection, irrespective of the initially infected organs, and arises from complex host immune, inflammatory, and coagulation responses to infecting microbes, resulting frequently in lethal shock with co- agulopathy and multiple organ failure (1, 2). In the United States alone, approximately 750,000 sepsis cases develop every year, and its frequency is increasing due to increases in the numbers of se- verely injured, aged, immune-suppressed, and terminal patients (3). Its overall mortality rate is still as high as 35% despite recent development in the treatment consisting of broad-spectrum antibi- otics, adequate fluid replenishment, and artificial support of organ function (3). Infection by polymicrobial flora in the intestine causes septic peritonitis with a higher mortality of 60–80% (4). Septic perito- nitis is characterized by a massive infiltration of neutrophils and macrophages into the peritoneal cavity. Their infiltration is indis- pensable for clearance of bacteria from the peritoneum, but their exaggerated activation can further augment systemic inflamma-...
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