CCR1 and CC chemokine ligand 5 interactions exacerbate innate immune responses during sepsis.
CCR1 has previously been shown to play important roles in leukocyte trafficking, pathogen clearance, and the type 1/type 2 cytokine balance, although very little is known about its role in the host response during sepsis. In a cecal ligation and puncture model of septic peritonitis, CCR1-deficient (CCR1(-/-)) mice were significantly protected from the lethal effects of sepsis when compared with wild-type (WT) controls. The peritoneal and systemic cytokine profile in CCR1(-/-) mice was characterized by a robust, but short-lived and regulated antibacterial response. CCR1 expression was not required for leukocyte recruitment, suggesting critical differences extant in the activation of WT and CCR1(-/-) resident or recruited peritoneal cells during sepsis. Peritoneal macrophages isolated from naive CCR1(-/-) mice clearly demonstrated enhanced cytokine/chemokine generation and antibacterial responses compared with similarly treated WT macrophages. CCR1 and CCL5 interactions markedly altered the inflammatory response in vivo and in vitro. Administration of CCL5 increased sepsis-induced lethality in WT mice, whereas neutralization of CCL5 improved survival. CCL5 acted in a CCR1-dependent manner to augment production of IFN-gamma and MIP-2 to damaging levels. These data illustrate that the interaction between CCR1 and CCL5 modulates the innate immune response during sepsis, and both represent potential targets for therapeutic intervention.
Ness
Traci L
TL
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Carpenter
Kristin J
KJ
Ewing
Jillian L
JL
Gerard
Craig J
CJ
Hogaboam
Cory M
CM
Kunkel
Steven L
SL
D000818:Animals; D001202:Ascitic Fluid / Q000166:cytology / Q000276:immunology / Q000473:pathology; D002432:Cecum; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018925:Chemokines / Q000096:biosynthesis; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology; D015169:Colony Count, Microbial; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate; D008026:Ligation; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010538:Peritonitis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D011677:Punctures; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018805:Sepsis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
C515301:Ccr1 protein, mouse; D018946:Chemokine CCL5; D018925:Chemokines; D016207:Cytokines; D016328:NF-kappa B; D054389:Receptors, CCR1; D019707:Receptors, Chemokine