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

CC chemokine receptor (CCR)4, a high affinity receptor for the CC chemokine s thymus and activation-regulated chemokine (TARC) and macrophage-derived c hemokine (MDC), is expressed in the thymus and spleen, and also by peripher al blood T cells, macrophages, platelets, and basophils. Recent studies hav e shown that CCR4 is the major chemokine receptor expressed by T helper typ e 2 (Th2) polarized cells. To study the in vivo role of CCR4, we have gener ated CCR4-deficient (CCR4(-/-)) mice by gene targeting. CCR4(-/-) mice deve loped 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)-1 alpha. The CCR4 deletion had no effect on Th2 differentiation in vitro or in a Th2-dependent model of allergic airway inf lammation. However, CCR4(-/-) mice exhibited significantly decreased mortal ity 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 1 beta, and MIP-1 alpha were r educed in CCR4(-/-) mice, and decreased expression of MDC and MIP-2 mRNA wa s 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.