Shinobu Saijo

Chiba University, Tiba, Chiba, Japan

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Publications (73)532.21 Total impact

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    ABSTRACT: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for various hematopoietic disorders. Graft-versus-host disease (GVHD) and infections are the major obstacles of HSCT, and their close relationship has been suggested. Although roles of bacterial and viral infections in the pathophysiology of GVHD are well described, impacts of fungal infection on GVHD remain to be elucidated. In mouse models of GVHD, injection of α-Mannan, a major component of fungal cell wall, or heat-killed Candida albicans exacerbated GVHD, particularly in the lung. α-Mannan induced donor T cell polarization towards Th17 and lung specific chemokine environment in GVHD led to accumulation of Th17 cells in the lung. The detrimental effects of α-Mannan on GVHD depended on donor IL-17A production and host c-type lectin receptor Dectin-2. These results suggest a previously unrecognized link between pulmonary GVHD and fungal infection following allogeneic HSCT. Copyright © 2015 American Society of Hematology.
    Blood 03/2015; DOI:10.1182/blood-2014-12-615781 · 10.43 Impact Factor
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    ABSTRACT: Transplant recipients on calcineurin inhibitors are at high risk of invasive fungal infection. Understanding how calcineurin inhibitors impair fungal immunity is a key priority for defining risk of infection. Here, we show that the calcineurin inhibitor tacrolimus impairs clearance of the major mould pathogen Aspergillus fumigatus from the airway, by inhibiting macrophage inflammatory responses. This leads to defective early neutrophil recruitment and fungal clearance. We confirm these findings in zebrafish, showing an evolutionarily conserved role for calcineurin signalling in neutrophil recruitment during inflammation. We find that calcineurin–NFAT activation is phagocytosis dependent and collaborates with NF-κB for TNF-α production. For yeast zymosan particles, activation of macrophage calcineurin–NFAT occurs via the phagocytic Dectin-1–spleen tyrosine kinase pathway, but for A. fumigatus, activation occurs via a phagosomal TLR9-dependent and Bruton's tyrosine kinase-dependent signalling pathway that is independent of MyD88. We confirm the collaboration between NFAT and NF-κB for TNF-α production in primary alveolar macrophages. These observations identify inhibition of a newly discovered macrophage TLR9–BTK–calcineurin–NFAT signalling pathway as a key immune defect that leads to organ transplant-related invasive aspergillosis.
    EMBO Molecular Medicine 01/2015; 7(3). DOI:10.15252/emmm.201404556 · 8.25 Impact Factor
  • Rikio Yabe, Yoichiro Iwakura, Shinobu Saijo
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    ABSTRACT: C-type lectin receptors (CLRs) are a group of pattern recognition receptors (PRRs) that recognize carbohydrate structures in microbes, including fungi and bacteria, as pathogen-associated molecular patterns (PAMPs). They are expressed mainly in dendritic cells (DCs) and macrophages, and among these CLRs, DC-associated C-type lectin-1 (Dectin-1), DC-associated C-type lectin-2 (Dectin-2), macrophage-inducible C-type lectin (Mincle), and macrophage C-type lectin (Mcl) transduce their signaling through phosphorylation of spleen tyrosine kinase (Syk). On the other hand, human DC-specific intracellular adhesion molecule 3-grabbing non-integrin (DC-SIGN) and its mouse homologue SIGN-related gene 3 (SIGNR3), members of the DC-SIGN superfamily of CLRs, transduce their signaling through intracellular tyrosine-containing motif. In addition to pathogen recognition, Mincle, DC-SIGN, and SIGNR3 have been shown to recognize molecules from self, suggesting pleiotropic roles of CLRs in the homeostasis of the body. Here, we review each of these receptors in detail describing their expression, ligand recognition, signaling, and associated human diseases.
    Glycoscience: Biology and Medicine, 01/2015: pages 1319-1329; , ISBN: 978-4-431-54840-9
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    ABSTRACT: Interleukin-17 (IL-17)-producing γδ T (γδ17) cells have been implicated in inflammatory diseases, but the underlying pathogenic mechanisms remain unclear. Here, we show that both CD4(+) and γδ17 cells are required for the development of autoimmune arthritis in IL-1 receptor antagonist (IL-1Ra)-deficient mice. Specifically, activated CD4(+) T cells direct γδ T-cell infiltration by inducing CCL2 expression in joints. Furthermore, IL-17 reporter mice reveal that the Vγ6(+) subset of CCR2(+) γδ T cells preferentially produces IL-17 in inflamed joints. Importantly, because IL-1Ra normally suppresses IL-1R expression on γδ T cells, IL-1Ra-deficient mice exhibit elevated IL-1R expression on Vγ6(+) cells, which play a critical role in inducing them to produce IL-17. Our findings demonstrate a pathogenic mechanism in which adaptive and innate immunity induce an autoimmune disease in a coordinated manner.
    Nature Communications 01/2015; 6:7464. DOI:10.1038/ncomms8464 · 10.74 Impact Factor
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    ABSTRACT: Dectin-2 is a C-type lectin receptor that recognizes high mannose polysaccharides. Cryptococcus neoformans, a yeast-form fungal pathogen, is rich in polysaccharides in its cell wall and capsule. In the present study, we analyzed the role of Dectin-2 in the host defense to C. neoformans infection. In Dectin-2 gene-disrupted (KO) mice, the clearance of this fungus and the inflammatory response, as shown by histological analysis and accumulation of leukocytes in the infected lungs, were comparable to those in wild-type (WT) mice. The production of Th2 cytokines in lungs was higher in Dectin-2KO mice than WT mice after infection, whereas there was no difference in the production of Th1, Th17 and proinflammatory cytokines between these mice. Mucin production was significantly increased in Dectin-2KO mice, and this increase was reversed by administration of anti-IL-4 mAb. The expression of β1-defensin, cathelicidin, surfactant protein (Sp)-A and Sp-D in the infected lungs was comparable between these mice. In in vitro experiments, IL-12p40 and TNF-α production and expression of CD86 and MHC class II by bone marrow-derived dendritic cells and alveolar macrophages was completely abrogated in Dectin-2KO mice. Finally, the disrupted lysates of C. neoformans, but not the whole yeast cells, activated Dectin-2-triggered signaling in an assay with NFAT-GFP reporter cells expressing this receptor. These results suggest that Dectin-2 may oppose Th2 response and IL-4-dependent mucin production in the lungs after infection with C. neoformans, and it may not be required for the production of Th1, Th17 and proinflammatory cytokines and clearance of this fungal pathogen. Copyright © 2014, American Society for Microbiology. All Rights Reserved.
    Infection and Immunity 11/2014; 83(2). DOI:10.1128/IAI.02835-14 · 4.16 Impact Factor
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    ABSTRACT: Destruction of the pulmonary epithelium is a major feature of lung diseases caused by the mould pathogen Aspergillus fumigatus. Although it is widely postulated that tissue invasion is governed by fungal proteases, A. fumigatus mutants lacking individual or multiple enzymes remain fully invasive, suggesting a concomitant requirement for other pathogenic activities during host invasion. In this study we discovered, and exploited, a novel, tissue non-invasive, phenotype in A. fumigatus mutants lacking the pH-responsive transcription factor PacC. Our study revealed a novel mode of epithelial entry, occurring in a cell wall-dependent manner prior to protease production, and via the Dectin-1 β-glucan receptor. ΔpacC mutants are defective in both contact-mediated epithelial entry and protease expression, and significantly attenuated for pathogenicity in leukopenic mice. We combined murine infection modelling, in vivo transcriptomics, and in vitro infections of human alveolar epithelia, to delineate two major, and sequentially acting, PacC-dependent processes impacting epithelial integrity in vitro and tissue invasion in the whole animal. We demonstrate that A. fumigatus spores and germlings are internalised by epithelial cells in a contact-, actin-, cell wall- and Dectin-1 dependent manner and ΔpacC mutants, which aberrantly remodel the cell wall during germinative growth, are unable to gain entry into epithelial cells, both in vitro and in vivo. We further show that PacC acts as a global transcriptional regulator of secreted molecules during growth in the leukopenic mammalian lung, and profile the full cohort of secreted gene products expressed during invasive infection. Our study reveals a combinatorial mode of tissue entry dependent upon sequential, and mechanistically distinct, perturbations of the pulmonary epithelium and demonstrates, for the first time a protective role for Dectin-1 blockade in epithelial defences. Infecting ΔpacC mutants are hypersensitive to cell wall-active antifungal agents highlighting the value of PacC signalling as a target for antifungal therapy.
    PLoS Pathogens 10/2014; 10(10):e1004413. DOI:10.1371/journal.ppat.1004413 · 8.14 Impact Factor
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    ABSTRACT: Mycobacteria possess various immunomodulatory molecules on the cell wall. Mannose-capped lipoarabinomannan (Man-LAM), a major lipoglycan of Mycobacterium tuberculosis, has long been known to have both inhibitory and stimulatory effects on host immunity. However, the direct Man-LAM receptor that explains its pleiotropic activities has not been clearly identified. Here, we report that a C-type lectin receptor Dectin-2 (gene symbol Clec4n) is a direct receptor for Man-LAM. Man-LAM activated bone-marrow-derived dendritic cells (BMDCs) to produce pro- and anti-inflammatory cytokines, whereas it was completely abrogated in Clec4n–/– BMDCs. Man-LAM promoted antigen-specific T cell responses through Dectin-2 on DCs. Furthermore, Man-LAM induced experimental autoimmune encephalitis (EAE) as an adjuvant in mice, whereas Clec4n–/– mice were resistant. Upon mycobacterial infection, Clec4n–/– mice showed augmented lung pathology. These results demonstrate that Dectin-2 contributes to host immunity against mycobacterial infection through the recognition of Man-LAM
    Immunity 09/2014; 41(3):402-413. · 19.75 Impact Factor
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    ABSTRACT: Mycobacteria possess various immunomodulatory molecules on the cell wall. Mannose-capped lipoarabinomannan (Man-LAM), a major lipoglycan of Mycobacterium tuberculosis, has long been known to have both inhibitory and stimulatory effects on host immunity. However, the direct Man-LAM receptor that explains its pleiotropic activities has not been clearly identified. Here, we report that a C-type lectin receptor Dectin-2 (gene symbol Clec4n) is a direct receptor for Man-LAM. Man-LAM activated bone-marrow-derived dendritic cells (BMDCs) to produce pro- and anti-inflammatory cytokines, whereas it was completely abrogated in Clec4n–/– BMDCs. Man-LAM promoted antigen-specific T cell responses through Dectin-2 on DCs. Furthermore, Man-LAM induced experimental autoimmune encephalitis (EAE) as an adjuvant in mice, whereas Clec4n–/– mice were resistant. Upon mycobacterial infection, Clec4n–/– mice showed augmented lung pathology. These results demonstrate that Dectin-2 contributes to host immunity against mycobacterial infection through the recognition of Man-LAM.
    Immunity 08/2014; 41(3):402-413. DOI:10.1016/j.immuni.2014.08.005 · 19.75 Impact Factor
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    ABSTRACT: eLife digest When cells in the body grow and divide uncontrollably, cancerous tumors can form. An individual's likelihood of recovering from cancer is highly variable and often depends on the type of cancer and the extent of the disease at the start of treatment. Researchers are therefore interested in discovering how the body responds against cancerous cells. The first line of defense against infection and disease is the body's innate immune system, which includes a suite of immune cells known as white blood cells. These cells patrol the body's organs and tissues in an effort to immediately respond to pathogens and damaged, stressed or otherwise abnormal host cells. Among white blood cells, natural killer cells are involved in identifying and destroying tumor cells. However, it was unclear whether or how other immune cells might help natural killer cells to destroy tumors. In addition, although immune cells detect pathogens and injured cells by producing proteins called pattern recognition receptors, it was unknown whether these receptors also detect tumor cells. Here, Chiba et al. reveal that two other types of immune cell—dendritic cells and macrophages—play essential roles in helping natural killer cells to prevent tumors from growing in mice. The dendritic cells and macrophages produce a pattern recognition receptor called Dectin-1 that recognizes a molecule found on the surface of some—but not all—types of tumor cell. In doing so, Dectin-1 activates a critical signaling pathway and directs the activity of the natural killer cells so that they can effectively kill tumor cells. Chiba et al. found that these tumors grew faster in mice that lack the Dectin-1 protein. The findings of Chiba et al. may also help to explain the effectiveness of certain antibodies—proteins that recognize and neutralize foreign objects such as bacteria and viruses—in cancer therapy. In addition, the Dectin-1 pathway presents a new avenue of research that may offer new cancer treatments. DOI: http://dx.doi.org/10.7554/eLife.04177.002
    eLife Sciences 08/2014; 3:e04177. DOI:10.7554/eLife.04177 · 8.52 Impact Factor
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    ABSTRACT: Dectin-1 is a membrane-bound pattern recognition receptor for β-glucans, which are the main constituents of fungal cell walls. Detection of β-glucans by dectin-1 triggers an effective innate immune response. In this study, we have used a systems biology approach to provide the first comprehensive characterization of the secretome and associated intracellular signaling pathways involved in activation of dectin-1/Syk in human macrophages. Transcriptome and secretome analysis revealed that the dectin-1 pathway induced significant gene expression changes and robust protein secretion in macrophages. The enhanced protein secretion correlated only partly with increased gene expression. Bioinformatics combined with functional studies revealed that the dectin-1/Syk pathway activates both conventional and unconventional, vesicle-mediated, protein secretion. The unconventional protein secretion triggered by the dectin-1 pathway is dependent on inflammasome activity and an active autophagic process. In conclusion, our results reveal that unconventional protein secretion has an important role in the innate immune response against fungal infections.
    The Journal of Immunology 05/2014; 192(12). DOI:10.4049/jimmunol.1303213 · 5.36 Impact Factor
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    ABSTRACT: Rationale: The fact that sensitization against fungi is closely related to the severity of asthma suggests that immune systems recognizing fungi are involved in the pathogenesis of severe asthma. Recently, Dectin-2 (gene symbol Clec4n), a C-type lectin receptor, has been shown to function as not only a major pattern recognition receptor for fungi but also a receptor for some components of house dust mite (HDM) extract, a major allergen for asthma. However, the roles of Dectin-2 in the induction of HDM-induced allergic airway inflammation remain largely unknown. Objectives: To determine the roles of Dectin-2 in HDM-induced allergic airway inflammation. Methods: We examined the roles of Dectin-2 in the induction of HDM-induced Th2 and Th17 cell differentiation and subsequent allergic airway inflammation by using Clec4n-deficient (Clec4n-/-) mice. We also investigated Dectin-2-expressing cells in the lung and their roles in HDM-induced allergic airway inflammation. Main Results: Clec4n-/- mice showed significantly attenuated HDM-induced allergic airway inflammation and decreased Th2 and Th17 cell differentiation. Dectin-2 mRNA, together with Dectin-3 and FcRγ mRNAs, was expressed in CD11b+ dendritic cells (DCs) but not in CD4+ T cells or epithelial cells in the lung. CD11b+ DCs isolated from Clec4n-/- mice expressed lower levels of proinflammatory cytokines and co-stimulatory molecules which could lead to Th2 and Th17 cell differentiation than those from wild-type (WT) mice. HDM-pulsed Clec4n-/- DCs were less efficient for the induction of allergic airway inflammation than HDM-pulsed WT DCs. Conclusion: Dectin-2 expressed on CD11b+ DCs promotes HDM-induced Th2 and Th17 cell differentiation and allergic airway inflammation.
    American Journal of Respiratory Cell and Molecular Biology 03/2014; DOI:10.1165/rcmb.2013-0522OC · 4.11 Impact Factor
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    ABSTRACT: CpG DNA, a ligand for Toll-like receptor 9 (TLR9), has been one of the most promising immunotherapeutic agents. Although there are several types of potent humanized CpG oligodeoxynucleotide (ODN), developing "all-in-one" CpG ODNs activating both B cells and plasmacytoid dendritic cells forming a stable nanoparticle without aggregation has not been successful. In this study, we generated a novel nanoparticulate K CpG ODN (K3) wrapped by the nonagonistic Dectin-1 ligand schizophyllan (SPG), K3-SPG. In sharp contrast to K3 alone, K3-SPG stimulates human peripheral blood mononuclear cells to produce a large amount of both type I and type II IFN, targeting the same endosome where IFN-inducing D CpG ODN resides without losing its K-type activity. K3-SPG thus became a potent adjuvant for induction of both humoral and cellular immune responses, particularly CTL induction, to coadministered protein antigens without conjugation. Such potent adjuvant activity of K3-SPG is attributed to its nature of being a nanoparticle rather than targeting Dectin-1 by SPG, accumulating and activating antigen-bearing macrophages and dendritic cells in the draining lymph node. K3-SPG acting as an influenza vaccine adjuvant was demonstrated in vivo in both murine and nonhuman primate models. Taken together, K3-SPG may be useful for immunotherapeutic applications that require type I and type II IFN as well as CTL induction.
    Proceedings of the National Academy of Sciences 02/2014; DOI:10.1073/pnas.1319268111 · 9.81 Impact Factor
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    ABSTRACT: The myeloid C-type lectin receptor Dectin-2 directs the generation of Th2 and Th17 immune responses to the house dust mite Dermatophagoides farinae through the generation of cysteinyl leukotrienes and proinflammatory cytokines, respectively, but a role for Dectin-2 in effector phase responses has not been described. In this study, we demonstrate that administration of the Dectin-2 mAb solely at the time of D. farinae challenge abrogated eosinophilic and neutrophilic inflammation in the bronchoalveolar lavage fluid and Th1, Th2, and Th17 inflammation in the lung of previously sensitized mice. Furthermore, Dectin-2 null mice (Clec4n(-/-)) sensitized with the adoptive transfer of D. farinae-pulsed wild-type (WT) bone marrow-derived dendritic cells (DCs) also had less D. farinae-elicited pulmonary inflammation, supporting an effector function for Dectin-2. The protection from pulmonary inflammation seen with the Dectin-2 mAb or in Clec4n(-/-) mice was associated with little or no reduction in lung-draining lymph node cells or their cytokine production and with no reduction in serum IgE. WT and Clec4n(-/-) mice recipients, sensitized with D. farinae-pulsed WT bone marrow-derived DCs, had comparable levels of D. farinae-elicited IL-6, IL-23, TNF-α, and cysteinyl leukotrienes in the lung. By contrast, D. farinae-elicited CCL4 and CCL8 production from pulmonary CD11c(+)CD11b(+)Ly6C(+) and CD11c(+)CD11b(+)Ly6C(-)CD64(+) monocyte-derived DCs was reduced in Clec4n(-/-) recipients. Addition of CCL8 at the time of D. farinae challenge abrogated the protection from eosinophilic, neutrophilic, and Th2 pulmonary inflammation seen in Clec4n(-/-) recipients. Taken together, these results reveal that Dectin-2 regulates monocyte-derived DC function in the pulmonary microenvironment at D. farinae challenge to promote the local inflammatory response.
    The Journal of Immunology 01/2014; 192(4). DOI:10.4049/jimmunol.1301809 · 5.36 Impact Factor
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    ABSTRACT: IL-1R antagonist-deficient (Il1rn(-/-)) mice develop autoimmune arthritis in which IL-17A plays a crucial role. Although many studies have shown that Th17 cell differentiation is dependent on TGF-β and IL-6, we found that Th17 cells developed normally in Il1rn(-/-)Il6(-/-) mice in vivo. Then, we analyzed the mechanisms of Th17 cell differentiation in Il1rn(-/-)Il6(-/-) mice. We found that IL-21 production was increased in the lymph nodes of Il1rn(-/-) mice, naive Il6(-/-) CD4(+) T cells differentiated into Th17 cells when cultured with TGF-β and IL-21, and the differentiation was greatly enhanced when IL-1 was added to the culture. Th17 cell differentiation was not induced by either TGF-β or IL-1 alone or in combination. IL-21 induced IL-1R expression in naive CD4(+) T cells, and IL-1 inhibited TGF-β-induced Foxp3 expression, resulting in the promotion of Th17 cell differentiation. Furthermore, IL-1 augmented the expression of Th17 cell-specific transcription factors such as Nfkbiz and Batf. These results indicate that excess IL-1 signaling can overcome the requirement of IL-6 in the differentiation of Th17 cells by suppressing Foxp3 expression and inducing Th17 cell-specific transcription factors.
    The Journal of Immunology 01/2014; 192(4). DOI:10.4049/jimmunol.1300387 · 5.36 Impact Factor
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    ABSTRACT: Vaccine immunity to the endemic mycoses of North America requires Th17 cells, but the pattern recognition receptors and signaling pathways that drive these protective responses have not been defined. We show that C-type lectin receptors exert divergent contributions to the development of antifungal Th17 cells and vaccine resistance against Blastomyces dermatitidis, Histoplasma capsulatum, and Coccidioides posadasii. Acquired immunity to B. dermatitidis requires Dectin-2, whereas vaccination against H. capsulatum and C. posadasii infection depends on innate sensing by Dectin-1 and Dectin-2, but not Mincle. Tracking Ag-specific T cells in vivo established that the Card9 signaling pathway acts indispensably and exclusively on differentiation of Th17 cells, while leaving intact their activation, proliferation, survival, and migration. Whereas Card9 signaling is essential, C-type lectin receptors offer distinct and divergent contributions to vaccine immunity against these endemic fungal pathogens. Our work provides new insight into innate immune mechanisms that drive vaccine immunity and Th17 cells.
    The Journal of Immunology 01/2014; 192(3). DOI:10.4049/jimmunol.1302314 · 5.36 Impact Factor
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    ABSTRACT: Il1rn(-/-) mice spontaneously develop arthritis and aortitis by an autoimmune mechanism and also develop dermatitis by an autoinflammatory mechanism. Here, we show that Rag2(-/-)Il1rn(-/-) mice develop spontaneous colitis with high mortality, making a contrast to the suppression of arthritis in these mice. Enhanced IL-17A expression in group 3 innate lymphoid cells (ILC3s) was observed in the colon of Rag2(-/-)Il1rn(-/-) mice. IL-17A-deficiency prolonged the survival of Rag2(-/-)Il1rn(-/-) mice, suggesting a pathogenic role of this cytokine in the development of intestinal inflammation. Although IL-17A-producing T cells were increased in Il1rn(-/-) mice, these mice did not develop colitis, because CD4(+)Foxp3(+) regulatory T cell population was also expanded. Thus, excess IL-1 signaling and IL-1-induced IL-17A from ILC3s cause colitis in Rag2(-/-)Il1rn(-/-) mice in which Treg cells are absent. These observations suggest that the balance between IL-17A-producing cells and Treg cells is important to keep the immune homeostasis of the colon.
    Experimental Animals 01/2014; 63(2):235-46. DOI:10.1538/expanim.63.235 · 1.17 Impact Factor
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    ABSTRACT: Rheumatoid arthritis (RA) is an autoimmune inflammatory disease exhibited most commonly in joints. We found that the expression of C1qtnf3, which encodes C1q/TNF-related protein 3 (CTRP3), was highly increased in two mouse RA models with different etiology. To elucidate the pathogenic roles of CTRP3 in the development of arthritis, we generated C1qtnf3(-/-) mice and examined the development of collagen-induced arthritis in these mice. We found that the incidence and severity score was higher in C1qtnf3(-/-) mice compared with wild-type (WT) mice. Histopathology of the joints was also more severe in C1qtnf3(-/-) mice. The levels of antibodies against type II collagen and pro-inflammatory cytokine mRNAs in C1qtnf3(-/-) mice were higher than WT mice. These observations indicate that CTRP3 plays an important role in the development of autoimmune arthritis, suggesting CTRP3 as a possible medicine to treat RA.
    Biochemical and Biophysical Research Communications 11/2013; 443(1). DOI:10.1016/j.bbrc.2013.11.040 · 2.28 Impact Factor
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    ABSTRACT: Although thymus-independent type 2 antigens generally do not undergo Ig class switching from IgM to IgG, pneumococcal polysaccharide vaccine (PPV) induces the production of serotype-specific IgG. How this happens remains unclear, however. In the present study, PPV immunization induced production of IgG as well as IgM specific for a serotype 3-pneumococcal polysaccharide in the sera of wild-type (WT) mice, but this phenomenon was significantly reduced in Dectin-2 knockout (KO) mice. Immunization with PPV caused IL-12p40 production in WT mice, but this response was significantly reduced in Dectin-2KO mice. Likewise, immunization with PPV activated natural killer T (NKT) cells in WT mice but not in Dectin-2KO mice. Furthermore, administration of α-galactosylceramide, recombinant (r)IL-12 or rIFN-γ improved the reduced IgG levels in Dectin-2KO mice, and treatment with neutralizing anti-IFN-γ mAb resulted in the reduction of IgG synthesis in PPV-immunized WT mice. Transfer of spleen cells from PPV-immunized WT mice conferred protection against pneumococcal infection on recipient mice, whereas this effect was cancelled when the transferred spleen cells were harvested from PPV-immunized Dectin-2KO mice. These results suggest that the detection of PPV antigens via Dectin-2 triggers IL-12 production, which induces IFN-γ synthesis by NKT cells and subsequently the production of serotype-specific IgG.
    PLoS ONE 10/2013; 8(10):e78611. DOI:10.1371/journal.pone.0078611 · 3.53 Impact Factor
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    ABSTRACT: Various C-type lectin receptors (CLRs), including Mincle and Dectin-2, function as pattern recognition receptors and play a central role in immunity to fungal pathogens. However, the precise structures of the CLR ligands in various pathogenic fungi have yet to be completely defined. Here we report that Malassezia, an opportunistic skin fungal pathogen, is cooperatively recognized by Mincle and Dectin-2 through distinct ligands. Solvent-based fractionation revealed that Mincle and Dectin-2 recognize lipophilic and hydrophilic components of Malassezia, respectively. Mass spectrometry and nuclear magnetic resonance (NMR) revealed glyceroglycolipid and unique mannosyl fatty acids linked to mannitol as two Mincle ligands. An O-linked mannobiose-rich glycoprotein was identified as a Malassezia ligand for Dectin-2. Cytokine production in response to the Mincle ligands and the Dectin-2 ligand was abrogated in Mincle(-/-) and Dectin-2(-/-) dendritic cells, respectively. These results demonstrate that Mincle and Dectin-2 recognize distinct ligands in Malassezia to induce host immune responses.
    Cell host & microbe 04/2013; 13(4):477-88. DOI:10.1016/j.chom.2013.03.008 · 12.19 Impact Factor
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    ABSTRACT: Inflammatory autoimmune diseases such as systemic lupus erythematosus (SLE) and polyarthritis are characterized by chronic cytokine overproduction, suggesting that the stimulation of host innate immune responses, speculatively by persistent infection or self nucleic acids, plays a role in the manifestation of these disorders. Mice lacking DNase II die during embryonic development through comparable inflammatory disease because phagocytosed DNA from apoptotic cells cannot be adequately digested and intracellular host DNA sensor pathways are engaged, resulting in the production of a variety of cytokines including type I IFN. The cellular sensor pathway(s) responsible for triggering DNA-mediated inflammation aggravated autoimmune disease remains to be determined. However, we report here that Stimulator of IFN Genes (STING) is responsible for inflammation-related embryonic death in DNase II defective mice initiated by self DNA. DNase II-dependent embryonic lethality was rescued by loss of STING function, and polyarthritis completely prevented because cytosolic DNA failed to robustly trigger cytokine production through STING-controlled signaling pathways. Our data provides significant molecular insight into the causes of DNA-mediated inflammatory disorders and affords a target that could plausibly be therapeutically controlled to help prevent such diseases.
    Proceedings of the National Academy of Sciences 11/2012; 109(47). DOI:10.1073/pnas.1215006109 · 9.81 Impact Factor

Publication Stats

3k Citations
532.21 Total Impact Points

Institutions

  • 2011–2015
    • Chiba University
      • Medical Mycology Research Center (MMRC)
      Tiba, Chiba, Japan
  • 2013–2014
    • Japan Science and Technology Agency (JST)
      Edo, Tōkyō, Japan
  • 1995–2014
    • The University of Tokyo
      • • Center for Experimental Medicine and Systems Biology
      • • Department of Microbiology and Immunology
      • • International Medical Center
      • • Institute of Medical Science
      Tōkyō, Japan
  • 2009
    • Tokyo University of Pharmacy and Life Science
      • School of Pharmacy
      Edo, Tōkyō, Japan
  • 2000
    • National Institute of Animal Health
      Ōsaka, Ōsaka, Japan
  • 1993
    • Kohno Clinical Medicine Research Institute
      Edo, Tōkyō, Japan