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)-1α. 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 α, interleukin 1β, and MIP-1α 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.

Chemokine receptor Ccr5 deficiency induces alternative macrophage activation and improves long‐term renal allograft outcome

“…Furthermore, at 42 days Foxp3 was significantly lower in grafts from Ccr5 À/À than WT recipients. A similar expression pattern was observed for the chemokine receptor Ccr4, which is found on Th2 cells and Treg and involved in mediating their immunosuppressive effects [27,28]. The chemokine receptor Ccr7, which is upregulated in mature DC and also required for the in vivo function of Treg [29], showed significantly lower expression levels in Ccr5 À/À recipients at 42 days, but not at 7 days.…”

Role of CCR4 Ligands, CCL17 and CCL22, During Schistosoma mansoni Egg-Induced Pulmonary Granuloma Formation in Mice

“…18 Later studies indicated that CCL22 was responsible for progressive increase in CCR4-positive cells in more chronic allergic airway responses to ovalbumin. 22 The relative role of CCL17 and CCL22 in these responses has been questioned by other data showing that targeting CCR4 either by gene deletion 20 or specific antibody 21 fails to prevent the development of allergic airway responses although CCR4 does appear to be involved in the maintenance of chronic allergic responses to Aspergillus fumigatus. 23 The present study confirmed that CCL22 and CCL17, in part, are critical for the development of aggressive Th2 granulomatous responses in the lung.…”

“…For example, increased CCR4 8 -11 and its corresponding ligands CCL17 (TARC) [12][13][14][15][16] and CCL22 (MDC) 14,15,17 have been detected in various clinical samples from asthmatic and allergic patients. However, the relative role for these chemokines and its receptor in experimental forms of these diseases remains controversial because some groups report a role for CCL17 18 and CCL22 19 but a lack 20,21 or partial 22,23 role for CCR4 during Th2-type cytokine-driven allergic airway responses in mice.…”

Basophil Responses to Chemokines Are Regulated by Both Sequential and Cooperative Receptor Signaling

“…Curiously, at higher concentrations, MDC appeared to cause a reduction in the baseline numbers of basophils that were in the high FSC gate, an effect not seen with other chemokines. This may reflect basophil responses mediated by another MDC receptor, the existence of which has been speculated in other work (56).…”