Shinobu Saijo

Chiba University, Tiba, Chiba, Japan

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Publications (64)451.04 Total impact

  • [Show abstract] [Hide abstract]
    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; · 19.80 Impact Factor
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    ABSTRACT: The eradication of tumor cells requires communication to and signaling by cells of the immune system. Natural killer (NK) cells are essential tumor-killing effector cells of the innate immune system; however, little is known about whether or how other immune cells recognize tumor cells to assist NK cells. Here, we show that the innate immune receptor Dectin-1 expressed on dendritic cells and macrophages is critical to NK-mediated killing of tumor cells that express N-glycan structures at high levels. Receptor recognition of these tumor cells causes the activation of the IRF5 transcription factor and downstream gene induction for the full-blown tumoricidal activity of NK cells. Consistent with this, we show exacerbated in vivo tumor growth in mice genetically deficient in either Dectin-1 or IRF5. The critical contribution of Dectin-1 in the recognition of and signaling by tumor cells may offer new insight into the anti-tumor immune system with therapeutic implications.
    eLife. 08/2014;
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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; · 4.15 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; · 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; · 5.52 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; · 5.52 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. · 1.46 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; · 2.41 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. · 13.02 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 01/2013; 8(10):e78611. · 3.53 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; · 9.81 Impact Factor
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    ABSTRACT: Introduction A high proportion of IL-17-producing gamma-delta T (gd17) cells was detected in joints of Il1rn−/− mice, a model of rheumatoid arthritis, whose development depends on IL-17 and T cells. However, their pathogenic roles are not well understood. Methods We assessed the effect of gdT cell or CD4+T cell depletion in Il1rn−/− mice using a monoclonal antibodies. Then, we examined the pathogenic activity of gd17 cells by adoptive transfer. Results To clarify the roles of gdT cells and CD4+ T cells in the development of arthritis, gdT cells or CD4+ T cells were depleted in Il1rn−/− miceusing antibodies. The development of disease was suppressed in both cases, suggesting both gdT cells and CD4+ T cells were involved in the pathogenesis. Then, the pathogenic role of gd17 cells in the absence of Th17 cells was examined. We generated mice with gd17 cells, but without Th17 cells, by adoptively transferring Il17−/−Il1rn−/−-CD4+ T cells into nu/nu mice in which gd17 cells are present. We found that these mice still developed arthritis and that only gdT cells produced IL-17. To corroborate that the development of arthritis in this transfer system is dependent on IL-17, we adoptively transferred Il17−/−Il1rn−/−-CD4+ T cells into Il17−/−-nu/nu mice. The development of arthritis was significantly suppressed in Il17−/−-nu/nu mice transferred with Il17−/−Il1rn−/−-CD4+ T cells compared with Il17+/+-nu/nu mice transferred with Il17−/−Il1rn−/−-CD4+ T cells, suggesting that extrathymic gd17 cells are also important for the development of arthritis. Interestingly, Il1rn−/− mice on the nu/nu mice background, in which only gd17 cells but not thymus-derived T cells are present, also developed arthritis. Thus, gd17 cells alone can induce arthritis without involvement of CD4+ T cells only in Il1rn−/− background mice in which excess IL-1 signaling is introduced. In contrast, a combination of CD4+ T cells and gd17 cells was required for the development of arthritis when scid/scid mice were used as recipients. These observations suggest that gd17 cells are required for the amplification of inflammation and CD4+ T cells direct the tissue specificity. Conclusion These results indicate that gdT cell-derived IL-17 plays an important role in the pathogenesis of arthritis in Il1rn−/−mice.
    Cytokine 09/2012; 59(3):514. · 2.52 Impact Factor
  • Arthritis Research & Therapy 02/2012; 14(1). · 4.30 Impact Factor
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    ABSTRACT: β-glucans have been reported to function as a potent adjuvant to stimulate innate and adaptive immune responses. However, β-glucans from different sources are differential in their structure, conformation, and thus biologic activity. Different preparations of β-glucans, soluble versus particulate, further complicate their mechanism of action. Here we show that yeast-derived particulate β-glucan activated dendritic cells (DCs) and macrophages via a C-type lectin receptor dectin-1 pathway. Activated DCs by particulate β-glucan promoted Th1 and cytotoxic T-lymphocyte priming and differentiation in vitro. Treatment of orally administered yeast-derived particulate β-glucan elicited potent antitumor immune responses and drastically down-regulated immunosuppressive cells, leading to the delayed tumor progression. Deficiency of the dectin-1 receptor completely abrogated particulate β-glucan-mediated antitumor effects. In contrast, yeast-derived soluble β-glucan bound to DCs and macrophages independent of the dectin-1 receptor and did not activate DCs. Soluble β-glucan alone had no therapeutic effect but significantly augmented antitumor monoclonal antibody-mediated therapeutic efficacy via a complement activation pathway but independent of dectin-1 receptor. These findings reveal the importance of different preparations of β-glucans in the adjuvant therapy and allow for the rational design of immunotherapeutic protocols usable in clinical trials.
    Blood 06/2011; 117(25):6825-36. · 9.78 Impact Factor
  • Shinobu Saijo, Yoichiro Iwakura
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    ABSTRACT: Dectin-1 and Dectin-2 are type II transmembrane proteins of the C-type lectin family with single carbohydrate recognition domains (CRDs) in their extracellular region. They are expressed mainly in dendritic cells and macrophages. Dectin-1 recognizes β-glucans with its CRD and transduces signals through its immunoreceptor tyrosine-based activation motif (ITAM)-like motif in the cytoplasmic domain, whereas Dectin-2 recognizes α-mannans and transduces its signal through association with the ITAM-containing Fc receptor γ chain. Upon ligand binding, spleen tyrosine kinase is recruited to the ITAM and activates the caspase recruitment domain family member 9 (CARD9)-nuclear factor-κB axis, resulting in the activation of various genes including those encoding pro-inflammatory cytokines. Both β-glucans and α-mannans are major cell wall components of fungi including Candida albicans and Pneumocystis carinii. Recently, it was reported that Dectin-1 is important in protection against P. carinii by inducing reactive oxygen species, whereas both Dectin-1 and Dectin-2 play important roles in defense against C. albicans by preferentially inducing T(h)17 cell differentiation. In this review, we briefly revisit the structures, ligands, signal transduction and functional roles of Dectin-1 and Dectin-2 in host defense against fungal infection.
    International Immunology 06/2011; 23(8):467-72. · 3.14 Impact Factor
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    ABSTRACT: Aspergillus fumigatus is commonly associated with allergic bronchopulmonary aspergillosis in patients with severe asthma in which chronic airway neutrophilia predicts a poor outcome. We were able to recapitulate fungus-induced neutrophilic airway inflammation in a mouse model in our efforts to understand the underlying mechanisms. However, neutrophilia occurred in a mouse strain-selective fashion, providing us with an opportunity to perform a comparative study to elucidate the mechanisms involved. Here we show that TNF-α, largely produced by Ly6c(+)CD11b(+) dendritic cells (DCs), plays a central role in promoting IL-17A from CD4(+) T cells and collaborating with it to induce airway neutrophilia. Compared with C57BL/6 mice, BALB/c mice displayed significantly more TNF-α-producing DCs and macrophages in the lung. Lung TNF-α levels were drastically reduced in CD11c-DTR BALB/c mice depleted of CD11c+ cells, and TNF-α-producing Ly6c(+)CD11b(+) cells were abolished in Dectin-1(-/-) and MyD88(-/-) BALB/c mice. TNF-α deficiency itself blunted accumulation of inflammatory Ly6c(+)CD11b(+) DCs. Also, lack of TNF-α decreased IL-17A but promoted IL-5 levels, switching inflammation from a neutrophil to eosinophil bias resembling that in C57BL/6 mice. The TNF-α(low) DCs in C57BL/6 mice contained more NF-κB p50 homodimers, which are strong repressors of TNF-α transcription. Functionally, collaboration between TNF-α and IL-17A triggered significantly higher levels of the neutrophil chemoattractants keratinocyte cytokine and macrophage inflammatory protein 2 in BALB/c mice. Our study identifies TNF-α as a molecular switch that orchestrates a sequence of events in DCs and CD4 T cells that promote neutrophilic airway inflammation.
    Proceedings of the National Academy of Sciences 03/2011; 108(13):5360-5. · 9.81 Impact Factor
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    ABSTRACT: Pulmonary infection of mice with Aspergillus fumigatus induces concurrent T helper type 1 (Th1) and Th17 responses that depend on Toll-like receptor/MyD88 and Dectin-1, respectively. However, the mechanisms balancing Th1 and Th17 CD4 T cell populations during infection remain incompletely defined. In this study, we show that Dectin-1 deficiency disproportionally increases Th1 responses and decreases Th17 differentiation after A. fumigatus infection. Dectin-1 signaling in A. fumigatus-infected wild-type mice reduces IFN-γ and IL-12p40 expression in the lung, thereby decreasing T-bet expression in responding CD4 T cells and enhancing Th17 responses. Absence of IFN-γ or IL-12p35 in infected mice or T-bet in responding CD4 T cells enhances Th17 differentiation, independent of Dectin-1 expression, in A. fumigatus-infected mice. Transient deletion of monocyte-derived dendritic cells also reduces Th1 and boosts Th17 differentiation of A. fumigatus-specific CD4 T cells. Our findings indicate that Dectin-1-mediated signals alter CD4 T cell responses to fungal infection by decreasing the production of IL-12 and IFN-γ in innate cells, thereby decreasing T-bet expression in A. fumigatus-specific CD4 T cells and enabling Th17 differentiation.
    Journal of Experimental Medicine 02/2011; 208(2):369-81. · 13.21 Impact Factor
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    ABSTRACT: Fungal infections are affecting an increasing number of people, and the failure of current therapies in treating systemic infection has resulted in an unacceptably high mortality rate. It is therefore of importance that we understand immune mechanisms operating during fungal infections, in order to facilitate development of adjunctive immunotherapies for the treatment of these diseases. C-type lectin receptors (CLRs) are pattern recognition receptors (PRRs) that are critical for immune responses to fungi. Many of these receptors are coupled to Syk kinase, which allows these receptors to signal via CARD9 leading to NF-κB activation, which in turn contributes to the induction of both innate and adaptive immunity. Dectin-1, Dectin-2 and Mincle are all CLRs that share this common signalling mechanism and have been shown to play key roles in antifungal immunity. This review aims to update existing paradigms and summarise the most recent findings on these CLRs, their signal transduction mechanisms and the collaborations between these CLRs and other PRRs.
    European Journal of Immunology 02/2011; 41(2):276-81. · 4.97 Impact Factor
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    ABSTRACT: Interleukin-17A (IL-17A) is the signature cytokine of the recently identified T helper 17 (Th17) cell subset. IL-17 has six family members (IL-17A to IL-17F). Although IL-17A and IL-17F share the highest amino acid sequence homology, they perform distinct functions; IL-17A is involved in the development of autoimmunity, inflammation, and tumors, and also plays important roles in the host defenses against bacterial and fungal infections, whereas IL-17F is mainly involved in mucosal host defense mechanisms. IL-17E (IL-25) is an amplifier of Th2 immune responses. The functions of IL-17B, IL-17C, and IL-17D remain largely elusive. In this review, we describe the identified functions of each IL-17 family member and discuss the potential of these molecules as therapeutic targets.
    Immunity 02/2011; 34(2):149-62. · 19.80 Impact Factor
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    ABSTRACT: The ubiquitous fungus Aspergillus fumigatus is associated with chronic diseases such as invasive pulmonary aspergillosis in immunosuppressed patients and allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis or severe asthma. Because of constant exposure to this fungus, it is critical for the host to exercise an immediate and decisive immune response to clear fungal spores to ward off disease. In this study, we observed that rapidly after infection by A. fumigatus, alveolar macrophages predominantly express Arginase 1 (Arg1), a key marker of alternatively activated macrophages (AAMs). The macrophages were also found to express Ym1 and CD206 that are also expressed by AAMs but not NOS2, which is expressed by classically activated macrophages. The expression of Arg1 was reduced in the absence of the known signaling axis, IL-4Rα/STAT6, for AAM development. While both Dectin-1 and TLR expressed on the cell surface have been shown to sense A. fumigatus, fungus-induced Arg1 expression in CD11c(+) alveolar macrophages was not dependent on either Dectin-1 or the adaptor MyD88 that mediates intracellular signaling by most TLRs. Alveolar macrophages from WT mice efficiently phagocytosed fungal conidia, but those from mice deficient in Dectin-1 showed impaired fungal uptake. Depletion of macrophages with clodronate-filled liposomes increased fungal burden in infected mice. Collectively, our studies suggest that alveolar macrophages, which predominantly acquire an AAM phenotype following A. fumigatus infection, have a protective role in defense against this fungus.
    PLoS ONE 01/2011; 6(1):e15943. · 3.53 Impact Factor

Publication Stats

3k Citations
451.04 Total Impact Points

Institutions

  • 2011–2014
    • Chiba University
      • Medical Mycology Research Center (MMRC)
      Tiba, Chiba, Japan
  • 1999–2012
    • The University of Tokyo
      • • Institute of Medical Science
      • • Center for Experimental Medicine and Systems Biology
      • • International Medical Center
      Edo, Tōkyō, Japan
  • 2009
    • Tokyo University of Pharmacy and Life Science
      • School of Pharmacy
      Edo, Tōkyō, Japan
    • Saitama Medical University
      • Department of Infectious Diseases and Infection Control
      Saitama, Saitama-ken, Japan
  • 1993
    • Kohno Clinical Medicine Research Institute
      Edo, Tōkyō, Japan