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A key role for CC chemokine receptor 4 in lipopolysaccharide-induced endotoxic shock.

ABSTRACT: CC chemokine receptor (CCR)4, a high affinity receptor for the CC chemokines thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC), is expressed in the thymus and spleen, and also by peripheral blood T cells, macrophages, platelets, and basophils. Recent studies have shown that CCR4 is the major chemokine receptor expressed by T helper type 2 (Th2) polarized cells. To study the in vivo role of CCR4, we have generated CCR4-deficient (CCR4(-/-)) mice by gene targeting. CCR4(-/-) mice developed normally. Splenocytes and thymocytes isolated from the CCR4(-/-) mice failed to respond to the CCR4 ligands TARC and MDC, as expected, but also surprisingly did not undergo chemotaxis in vitro in response to macrophage inflammatory protein (MIP)-1alpha. The CCR4 deletion had no effect on Th2 differentiation in vitro or in a Th2-dependent model of allergic airway inflammation. However, CCR4(-/-) mice exhibited significantly decreased mortality on administration of high or low dose bacterial lipopolysaccharide (LPS) compared with CCR4(+/+) mice. After high dose LPS treatment, serum levels of tumor necrosis factor alpha, interleukin 1beta, and MIP-1alpha were reduced in CCR4(-/-) mice, and decreased expression of MDC and MIP-2 mRNA was detected in peritoneal exudate cells. Analysis of peritoneal lavage cells from CCR4(-/)- mice by flow cytometry also revealed a significant decrease in the F4/80(+) cell population. This may reflect a defect in the ability of the CCR4(-/-) macrophages to be retained in the peritoneal cavity. Taken together, our data reveal an unexpected role for CCR4 in the inflammatory response leading to LPS-induced lethality.

SUBMITTER: Chvatchko Y

PROVIDER: S-EPMC2193157 | biostudies-literature | 2000 May

REPOSITORIES: biostudies-literature

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A key role for CC chemokine receptor 4 in lipopolysaccharide-induced endotoxic shock.

Chvatchko Y Y Hoogewerf A J AJ Meyer A A Alouani S S Juillard P P Buser R R Conquet F F Proudfoot A E AE Wells T N TN Power C A CA

The Journal of experimental medicine 20000501 10

CC chemokine receptor (CCR)4, a high affinity receptor for the CC chemokines thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC), is expressed in the thymus and spleen, and also by peripheral blood T cells, macrophages, platelets, and basophils. Recent studies have shown that CCR4 is the major chemokine receptor expressed by T helper type 2 (Th2) polarized cells. To study the in vivo role of CCR4, we have generated CCR4-deficient (CCR4(-/-)) mice by gene targe ...[more]

PMID: 10811868

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Project description:ObjectiveDendritic cells (DCs) have long been recognized as potential therapeutic targets of rheumatoid arthritis (RA). Increasing evidence has showed that DCs are capable of suppressing autoimmunity by expanding FoxP3? regulatory T cells (T(reg)), which in turn exert immunosuppression by increasing TGF?-1. In the SKG mice, activated DC prime autoreactive T cells causing autoantibody production and an inflammatory arthritic response. Recently, we reported that CC-chemokine receptor-2 deficient (Ccr2?/?) mice had impaired DCs migration and reduced CD8?? DCs in the C57Bl/6J mice strain and that these mice were more susceptible to collagen antibody-induced arthritis (CAIA), compared to wild type mice. To examine the mechanism by which DCs contribute to the increased susceptibility of arthritis in Ccr2?/? mice, we tested the hypothesis that CD8?? DCs are protective (tolerogenic) against autoimmune arthritis by examining the role of CD8?? DCs in Ccr2?/? and SKG mice.MethodsTo examine the mechanism by which DCs defects lead to the development of arthritis, we used two murine models of experimental arthritis: collagen-induced arthritis (CIA) in DBA1/J mice and zymosan-induced arthritis in SKG mice. DBA1/J mice received recombinant fms-like tyrosine kinase 3 ligand (Flt3L) injections to expand endogenous DCs populations or adoptive transfers of CD8?? DCs.ResultsFlt3L-mediated expansion of endogenous CD8?? DCs resulted in heightened susceptibility of CIA. In contrast, supplementation with exogenous CD8?? DCs ameliorated arthritis in Ccr2?/? mice and enhanced TGF?1 production by T cells. Furthermore, SKG mice with genetic inactivation of CCR2 did not affect the numbers of DCs nor improve the arthritis phenotype.ConclusionCD8?? DCs were tolerogenic to the development of arthritis. CD8?? DCs deficiency heightened the sensitivity to arthritis in Ccr2?/? mice. Ccr2 deficiency did not alter the arthritic phenotype in SKG mice suggesting the arthritis in Ccr2?/? mice was T cell-independent.

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A key role for CC chemokine receptor 4 in lipopolysaccharide-induced endotoxic shock.

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A key role for CC chemokine receptor 4 in lipopolysaccharide-induced endotoxic shock.

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