Showing papers by "Sho Yamasaki published in 2015"
TL;DR: The results suggest that cholesterol crystals are an endogenous ligand for hMincle and that they activate innate immune responses.
105 citations
TL;DR: It is demonstrated that MCL interacts with Mincle to promote its surface expression through protein–protein interaction via its stalk region, thereby magnifying Mincle-mediated signaling.
Abstract: C-type lectin receptors expressed in APCs are recently defined pattern recognition receptors that play a crucial role in immune responses against pathogen-associated molecular patterns. Among pathogen-associated molecular patterns, cord factor (trehalose-6,6'-dimycolate [TDM]) is the most potent immunostimulatory component of the mycobacterial cell wall. Two C-type lectin receptors, macrophage-inducible C-type lectin (Mincle) and macrophage C-type lectin (MCL), are required for immune responses against TDM. Previous studies indicate that MCL is required for TDM-induced Mincle expression. However, the mechanism by which MCL induces Mincle expression has not been fully understood. In this study, we demonstrate that MCL interacts with Mincle to promote its surface expression. After LPS or zymosan stimulation, MCL-deficient bone marrow-derived dendritic cells (BMDCs) had a lower level of Mincle protein expression, although mRNA expression was comparable with wild-type BMDCs. Meanwhile, BMDCs from MCL transgenic mice showed an enhanced level of Mincle expression on the cell surface. MCL was associated with Mincle through the stalk region and this region was necessary and sufficient for the enhancement of Mincle expression. This interaction appeared to be mediated by the hydrophobic repeat of MCL, as substitution of four hydrophobic residues within the stalk region with serine (MCL(4S)) abolished the function to enhance the surface expression of Mincle. MCL(4S) mutant failed to restore the defective TDM responses in MCL-deficient BMDCs. These results suggest that MCL positively regulates Mincle expression through protein-protein interaction via its stalk region, thereby magnifying Mincle-mediated signaling.
100 citations
TL;DR: It is concluded that CLECSF8 plays a non-redundant role in anti-mycobacterial immunity in mouse and in man.
88 citations
TL;DR: An enantioselective synthesis of (+)-corynomycolic acid, and its elaboration to esters of trehalose, glucose and glycerol, is described and Glucose monomycolate is revealed to be a potent activator of both mouse and human Mincle.
51 citations
TL;DR: It is shown that expression of Mincle, particularly by cDCs, contributes to the control of splenic M. bovis BCG infection in mice.
Abstract: The macrophage-inducible C-type lectin Mincle has recently been identified to be a pattern recognition receptor sensing mycobacterial infection via recognition of the mycobacterial cell wall component trehalose-6',6-dimycolate (TDM). However, its role in systemic mycobacterial infections has not been examined so far. Mincle-knockout (KO) mice were infected intravenously with Mycobacterium bovis BCG to mimic the systemic spread of mycobacteria under defined experimental conditions. After intravenous infection with M. bovis BCG, Mincle-KO mice responded with significantly higher numbers of mycobacterial CFU in spleen and liver, while reduced granuloma formation was observed only in the spleen. At the same time, reduced Th1 cytokine production and decreased numbers of gamma interferon-producing T cells were observed in the spleens of Mincle-KO mice relative to the numbers in the spleens of wild-type (WT) mice. The effect of adoptive transfer of defined WT leukocyte subsets generated from bone marrow cells of zDC(+/DTR) mice (which bear the human diphtheria toxin receptor [DTR] under the control of the classical dendritic cell-specific zinc finger transcription factor zDC) to specifically deplete Mincle-expressing classical dendritic cells (cDCs) but not macrophages after diphtheria toxin application on the numbers of splenic and hepatic CFU and T cell subsets was then determined. Adoptive transfer experiments revealed that Mincle-expressing splenic cDCs rather than Mincle-expressing macrophages contributed to the reconstitution of attenuated splenic antimycobacterial immune responses in Mincle-KO mice after intravenous challenge with BCG. Collectively, we show that expression of Mincle, particularly by cDCs, contributes to the control of splenic M. bovis BCG infection in mice.
44 citations
TL;DR: Significantly, a truncated β-glucosyl diglyceride was shown to provide potent signalling through both human and mouse Mincle and could activate murine bone marrow derived dendritic cells.
39 citations
TL;DR: Data in the present study show that the Nod1 signaling pathway in non–bone marrow-derived cells contributes to the development of atherosclerosis.
Abstract: Atherosclerosis is essentially a vascular inflammatory process in the presence of an excess amount of lipid. We have recently reported that oral administration of a nucleotide-binding oligomerization domain (Nod)-1 ligand, FK565, induced vascular inflammation in vivo. No studies, however, have proven the association between Nod1 and atherosclerosis in vivo. To investigate a potential role of NOD1 in atherogenesis, we orally administered FK565 to apolipoprotein E knockout (Apoe(-/-)) mice for 4 wk intermittently and performed quantification of atherosclerotic lesions in aortic roots and aortas, immunohistochemical analyses, and microarray-based gene expression profiling of aortic roots. FK565 administration accelerated the development of atherosclerosis in Apoe(-/-) mice, and the effect was dependent on Nod1 in non-bone marrow origin cells by bone marrow transplantation experiments. Immunohistochemical studies revealed the increases in the accumulation of macrophages and CD3 T cells within the plaques in aortic roots. Gene expression analyses of aortic roots demonstrated a marked upregulation of the Ccl5 gene during early stage of atherogenesis, and the treatment with Ccl5 antagonist significantly inhibited the acceleration of atherosclerosis in FK565-administered Apoe(-/-) mice. Additionally, as compared with Apoe(-/-) mice, Apoe and Nod1 double-knockout mice showed reduced development of atherosclerotic lesions from the early stage as well as their delayed progression and a significant reduction in Ccl5 mRNA levels at 9 wk of age. Data in the present study show that the Nod1 signaling pathway in non-bone marrow-derived cells contributes to the development of atherosclerosis.
36 citations
TL;DR: The results suggest that Ly6Chi monocytes are recruited to FK565-activated endothelial cells to generate cardiac CD11c+ macrophages, which play a pivotal role in the pathogenesis of acute coronary arteritis.
Abstract: Objective—Nod1 is an intracellular pattern recognition receptor for bacterial peptidoglycan fragments. We previously reported that a synthetic Nod1 ligand, FK565, induced acute coronary arteritis i...
29 citations
TL;DR: This study characterised CLECSF8 expression in the mouse under naive and inflammatory conditions and characterised the FcRg adaptor, which is essential for surface expression and signalling through the SYK/CARD9 pathway.
Abstract: Background C-type lectin-like receptors (CTLRs) play critical roles in immunity and homeostasis by recognising a great variety of microbial or endogenous ligands [1] CLECSF8 is a member of the Dectin–2 family of CTLRs Previous research indicates that CLECSF8 associates with the FcRg adaptor, which is essential for surface expression and signalling through the SYK/CARD9 pathway Recently, the mycobacterial cord factor (TDM, trehalose-6,6’-dimycolate) was identified as the ligand of CLECSF8, as shown previously for the closely related CTLR Mincle [2] Indeed, we recently showed that CLECSF8 plays a critical role in human and murine anti-mycobacterial immunity [3] In this study, we characterised CLECSF8 expression in the mouse under naive and inflammatory conditions