title: Essential involvement of CX3CR1-mediated signals in the bactericidal host defense during septic peritonitis.
abstract: Cecal ligation and puncture (CLP) caused septic peritonitis in wild-type (WT) mice, with approximately 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-1beta, TNF-alpha, IFN-gamma, 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-1beta, TNF-alpha, IFN-gamma, and IL-12 by WT macrophages with NF-kappaB 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-kappaB signal pathway, with few effects on macrophage infiltration.
authors.affiliation: Department of Forensic Medicine and.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ishida
authors.forename: Takahito
authors.initials: T
authors.lastname: Hayashi
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Goto
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kimura
authors.forename: Shigeru
authors.initials: S
authors.lastname: Akimoto
authors.forename: Naofumi
authors.initials: N
authors.lastname: Mukaida
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Kondo