The chemokine receptor CCR6 is an important component of the innate immune response

In our initial studies we found that naÏve CCR6-deficient (CCR6 –/– ) C57BL/6 mice possessed significantly lower number of both F4/80 + macrophages and dendritic cells (DC), but higher number of B cells in the peritoneal cavity, as compared to naÏve wild type (WT) controls. Furthermore, peritoneal macrophages isolated from CCR6 –/– mice expressed significantly lower levels of inflammatory cytokines and nitric oxide following lipopolysaccharide (LPS)stimulation, as compared to WT macrophages. In a severe experimental peritonitis model induced by cecal ligation and puncture (CLP), CCR6 –/– mice were protected when compared with WT controls. At 24 h following the induction of peritonitis, CCR6 –/– mice exhibited significantly lower levels of inflammatory cytokines/chemokines in both the peritoneal cavity and blood. Interestingly, DC recruitment into the peritoneal cavity was impaired in CCR6 –/– mice during the evolution of CLP-induced peritonitis. Peritoneal macrophages isolated from surviving CCR6 –/– mice 3 days after CLP-induced peritonitis exhibited an enhanced LPS response compared with similarly treated WT peritoneal macrophages. These data illustrate that CCR6 deficiency alters the innate response via attenuating the hyperactive local and systemic inflammatory response during CLP-induced peritonitis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/56112/1/2487_ftp.pd

The Reduced Expression of 6ckine in the plt Mouse Results from the Deletion of One of Two 6ckine Genes

6Ckine is an unusual chemokine capable of attracting naive T lymphocytes in vitro. It has been recently reported that lack of 6Ckine expression in lymphoid organs is a prominent characteristic of mice homozygous for the paucity of lymph node T cell (plt) mutation. These mice show reduced numbers of T cells in lymph nodes, Peyer's patches, and the white pulp of the spleen. The genetic reason for the lack of 6Ckine expression in the plt mouse, however, has remained unknown. Here we demonstrate that mouse 6Ckine is encoded by two genes, one of which is expressed in lymphoid organs and is deleted in plt mice. A second 6Ckine gene is intact and expressed in the plt mouse

Human cytomegalovirus US28 facilitates cell-to-cell viral dissemination

Human cytomegalovirus (HCMV) encodes a number of viral proteins with homology to cellular G protein-coupled receptors (GPCRs). These viral GPCRs, including US27, US28, UL33, and UL78, have been ascribed numerous functions during infection, including activating diverse cellular pathways, binding to immunomodulatory chemokines, and impacting virus dissemination. To investigate the role of US28 during virus infection, two variants of the clinical isolate TB40/E were generated: TB40/E-US28(YFP) expressing a C-terminal yellow fluorescent protein tag, and TB40/E-FLAG(YFP) in which a FLAG-YFP cassette replaces the US28 coding region. The TB40/E-US28(YFP) protein localized as large perinuclear fluorescent structures at late times post-infection in fibroblasts, endothelial, and epithelial cells. Interestingly, US28(YFP) is a non-glycosylated membrane protein throughout the course of infection. US28 appears to impact cell-to-cell spread of virus, as the ΔUS28 virus (TB40/E-FLAG(YFP)) generated a log-greater yield of extracellular progeny whose spread could be significantly neutralized in fibroblasts. Most strikingly, in epithelial cells, where dissemination of virus occurs exclusively by the cell-to-cell route, TB40/E-FLAG(YFP) (ΔUS28) displayed a significant growth defect. The data demonstrates that HCMV US28 may contribute at a late stage of the viral life cycle to cell-to-cell dissemination of virus

Increased responsiveness of murine eosinophils to MIPâ 1β (CCL4) and TCAâ 3 (CCL1) is mediated by their specific receptors, CCR5 and CCR8

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141970/1/jlb1019.pd

Skin expression of IL-23 drives the development of psoriasis and psoriatic arthritis in mice

Psoriasis (PS) is a chronic skin inflammation. Up to 30% of the patients with PS develop psoriatic arthritis (PsA), a condition characterized by inflammatory arthritis that affects joints or entheses. Although there is mounting evidence for a critical role of interleukin-23 (IL-23) signaling in the pathogenesis of both PS and PsA, it remains unclear whether IL-23-induced skin inflammation drives joint disease. Here, we show that mice expressing increased levels of IL-23 in the skin (K23 mice) develop a PS-like disease that is characterized by acanthosis, parakeratosis, hyperkeratosis, and inflammatory infiltrates in the dermis. Skin disease preceded development of PsA, including enthesitis, dactylitis, and bone destruction. The development of enthesitis and dactylitis was not due to high circulating levels of IL-23, as transgenic animals and controls had similar levels of this cytokine in circulation. IL-22, a downstream cytokine of IL-23, was highly increased in the serum of K23 mice. Although IL-22 deficiency did not affect skin disease development, IL-22 deficiency aggravated the PsA-like disease in K23 mice. Our results demonstrate a central role for skin expressed IL-23 in the initiation of PS and on pathogenic processes leading to PsA.Fil: Chen, Lili. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Deshpande, Madhura. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Grisotto, Marcos. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Smaldini, Paola Lorena. Icahn School of Medicine at Mount Sinai; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; ArgentinaFil: Garcia, Roberto. Hospital for Special Surgery; Estados UnidosFil: He, Zhengxiang. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Gulko, Percio. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Lira, Sergio A.. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Furtado, Glaucia C.. Icahn School of Medicine at Mount Sinai; Estados Unido

Aberrant in vivo T helper type 2 cell response and impaired eosinophil recruitment in CC chemokine receptor 8 knockout mice

Chemokine receptors transduce signals important for the function and trafficking of leukocytes. Recently, it has been shown that CC chemokine receptor (CCR)8 is selectively expressed by Th2 subsets, but its functional relevance is unclear. To address the biological role of CCR8, we generated CCR8 deficient (-/-) mice. Here we report defective T helper type 2 (Th2) immune responses in vivo in CCR8 -/- mice in models of Schistosoma mansoni soluble egg antigen (SEA)-induced granuloma formation as well as ovalbumin (OVA)- and cockroach antigen (CRA)-induced allergic airway inflammation. In these mice, the response to SEA, OVA, and CRA showed impaired Th2 cytokine production that was associated with aberrant type 2 inflammation displaying a 50 to 80% reduction in eosinophils. In contrast, a prototypical Th1 immune response, elicited by Mycobacteria bovis purified protein derivative (PPD) was unaffected by CCR8 deficiency. Mechanistic analyses indicated that Th2 cells developed normally and that the reduction in eosinophil recruitment was likely due to systemic reduction in interleukin 5. These results indicate an important role for CCR8 in Th2 functional responses in vivo

Absence of CC chemokine receptor 8 enhances innate immunity during septic peritonitis

An effective clearance of microbes is crucial in host defense during infection. In the present study, we demonstrate that CC chemokine receptor 8 (CCR8) skews innate immune response during septic peritonitis induced by cecal ligation and puncture (CLP). CCR8 was expressed in resident peritoneal macrophages and elicited leukocytes during CLP in the wildâ type CCR8+/+ mice. CCR8â /â mice were resistant to CLPâ induced lethality relative to CCR8+/+ mice, and this resistance was associated with an augmented bacterial clearance in CCR8â /â mice. In vitro, peritoneal macrophages from CCR8â /â mice, but not neutrophils, exhibited enhanced bactericidal activities relative to those from CCR8+/+ mice. Upon stimulation with the bacterial component LPS, elevated levels of superoxide generation, lysosomal enzyme release, and nitric oxide generation, effector molecules for bacterial killing were detected in CCR8â /â macrophages relative to CCR8+/+ macrophages. In addition, CCR8â /â macrophages produced significantly higher levels than CCR8+/+ macrophages of several cytokines and chemokines known to augment bactericidal activities of leukocytes that include TNFâ α, ILâ 12, macrophageâ derived chemokine (MDC/CCL22), macrophage inflammatory protein (MIP)â 2, and KC. Altogether, these results indicate that CCR8 may have a negative impact on host defense during septic peritonitis, providing a new paradigm for the role of CCR8 in innate immunity.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154456/1/fsb2fj041728fje.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154456/2/fsb2fj041728fje-sup-0001.pd