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Dive into the research topics where Noriyuki Fujikado is active.

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Featured researches published by Noriyuki Fujikado.


Immunity | 2009

Differential Roles of Interleukin-17A and -17F in Host Defense against Mucoepithelial Bacterial Infection and Allergic Responses

Harumichi Ishigame; Shigeru Kakuta; Takeshi Nagai; Motohiko Kadoki; Aya Nambu; Yutaka Komiyama; Noriyuki Fujikado; Yuko Tanahashi; Aoi Akitsu; Hayato Kotaki; Katsuko Sudo; Susumu Nakae; Chihiro Sasakawa; Yoichiro Iwakura

Interleukin-17A (IL-17A) is a cytokine produced by T helper 17 (Th17) cells and plays important roles in the development of inflammatory diseases. Although IL-17F is highly homologous to IL-17A and binds the same receptor, the functional roles of this molecule remain largely unknown. Here, we demonstrated with Il17a(-/-), Il17f(-/-), and Il17a(-/-)Il17f(-/-) mice that IL-17F played only marginal roles, if at all, in the development of delayed-type and contact hypersensitivities, autoimmune encephalomyelitis, collagen-induced arthritis, and arthritis in Il1rn(-/-) mice. In contrast, both IL-17F and IL-17A were involved in host defense against mucoepithelial infection by Staphylococcus aureus and Citrobacter rodentium. IL-17A was produced mainly in T cells, whereas IL-17F was produced in T cells, innate immune cells, and epithelial cells. Although only IL-17A efficiently induced cytokines in macrophages, both cytokines activated epithelial innate immune responses. These observations indicate that IL-17A and IL-17F have overlapping yet distinct roles in host immune and defense mechanisms.


Immunity | 2010

Dectin-2 Recognition of α-Mannans and Induction of Th17 Cell Differentiation Is Essential for Host Defense against Candida albicans

Shinobu Saijo; Satoshi Ikeda; Keiko Yamabe; Shigeru Kakuta; Harumichi Ishigame; Aoi Akitsu; Noriyuki Fujikado; Toshimasa Kusaka; Sachiko Kubo; Soo-hyun Chung; Ryohei Komatsu; Noriko N. Miura; Yoshiyuki Adachi; Naohito Ohno; Kazutoshi Shibuya; Natsuo Yamamoto; Kazuyoshi Kawakami; Sho Yamasaki; Takashi Saito; Shizuo Akira; Yoichiro Iwakura

Dectin-2 (gene symbol Clec4n) is a C-type lectin expressed by dendritic cells (DCs) and macrophages. However, its functional roles and signaling mechanisms remain to be elucidated. Here, we generated Clec4n(-/-) mice and showed that this molecule is important for host defense against Candida albicans (C. albicans). Clec4n(-/-) DCs had virtually no fungal alpha-mannan-induced cytokine production. Dectin-2 signaling induced cytokines through an FcRgamma chain and Syk-CARD9-NF-kappaB-dependent signaling pathway without involvement of MAP kinases. The yeast form of C. albicans induced interleukin-1beta (IL-1beta) and IL-23 secretion in a Dectin-2-dependent manner. In contrast, cytokine production induced by the hyphal form was only partially dependent on this lectin. Both yeast and hyphae induced Th17 cell differentiation, in which Dectin-2, but not Dectin-1, was mainly involved. Because IL-17A-deficient mice were highly susceptible to systemic candida infection, this study suggests that Dectin-2 is important in host defense against C. albicans by inducing Th17 cell differentiation.


Nature Medicine | 2008

Dcir deficiency causes development of autoimmune diseases in mice due to excess expansion of dendritic cells.

Noriyuki Fujikado; Shinobu Saijo; Tomo Yonezawa; Kazusuke Shimamori; Akina Ishii; Sho Sugai; Hayato Kotaki; Katsuko Sudo; Masato Nose; Yoichiro Iwakura

The dendritic cell immunoreceptor (official gene symbol Clec4a2, called Dcir here) is a C-type lectin receptor expressed mainly in dendritic cells (DCs) that has a carbohydrate recognition domain in its extracellular portion and an immunoreceptor tyrosine–based inhibitory motif, which transduces negative signals into cells, in its cytoplasmic portion. We found high Dcir expression in the joints of two mouse rheumatoid arthritis models. Because the structural characteristics of Dcir suggest that it may have an immune regulatory role, and because autoimmune-related genes are mapped to the DCIR locus in humans, we generated Dcir−/− mice to learn more about the pathological roles of this molecule. We found that aged Dcir−/− mice spontaneously develop sialadenitis and enthesitis associated with elevated serum autoantibodies. Dcir−/− mice showed a markedly exacerbated response to collagen-induced arthritis. The DC population was expanded excessively in aged and type II collagen–immunized Dcir−/− mice. Upon treatment with granulocyte-macrophage colony–stimulating factor, Dcir−/− mouse–derived bone marrow cells (BMCs) differentiated into DCs more efficiently than did wild-type BMCs, owing to enhanced signal transducer and activator of transcription-5 phosphorylation. These observations indicate that Dcir is a negative regulator of DC expansion and has a crucial role in maintaining the homeostasis of the immune system.


Science | 2015

Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance

Siyoung Yang; Noriyuki Fujikado; Dmitriy Kolodin; Christophe Benoist; Diane Mathis

Early T cells keep autoimmunity at bay A major challenge faced by the immune system is to react to foreign substances, such as microbes, while simultaneously tolerating the self. Upsetting this balance leads to autoimmunity. Regulatory T cells (Tregs), are a subset of immune cells that help to maintain this balance. Yang et al. found that murine Treg cells generated very early in life are distinct from those generated in older animals and play an especially important role in keeping autoimmunity in check (see the Perspective by Tanaka and Sakaguchi). These changes are due to differences in the way Tregs develop in the thymus in newborn versus adult mice. Science, this issue p. 589; see also p. 506 Regulatory T cells generated in neonatal mice are especially important for preventing autoimmunity. [Also see Perspective by Tanaka and Sakaguchi] Aire is an important regulator of immunological tolerance, operating in a minute subset of thymic stromal cells to induce transcripts encoding peptides that guide T cell selection. Expression of Aire during a perinatal age window is necessary and sufficient to prevent the multiorgan autoimmunity characteristic of Aire-deficient mice. We report that Aire promotes the perinatal generation of a distinct compartment of Foxp3+CD4+ regulatory T (Treg) cells, which stably persists in adult mice. This population has a role in maintaining self-tolerance, a transcriptome and an activation profile distinguishable from those of Tregs produced in adults. Underlying the distinct Treg populations are age-dependent, Aire-independent differences in the processing and presentation of thymic stromal-cell peptides, resulting in different T cell receptor repertoires. Our findings expand the notion of a developmentally layered immune system.


International Immunology | 2010

IL-1 plays an important role in the bone metabolism under physiological conditions

Young-Mi Lee; Noriyuki Fujikado; Hiroko Manaka; Hisataka Yasuda; Yoichiro Iwakura

It is well known that IL-1 is involved in bone resorption under pathological conditions. The role of this cytokine in bone remodeling under physiological conditions, however, remains obscure. In this study, we addressed the role of IL-1 in physiological bone metabolism through analyses of IL-1α-deficient (KO), IL-1β KO and IL-1α/β double KO mice that were housed under specific pathogen free conditions. The femur mineral density, trabecular bone mass and cortical thickness significantly increased in all KO mice compared with wild-type (WT) mice. The number of osteoclasts in trabecular bones decreased, suggesting that IL-1 regulates bone metabolism through regulation of osteoclast formation. When differentiation of bone marrow (BM) cells into osteoclasts was induced by parathyroid hormone in co-cultures of osteoblasts and BM cells from WT and IL-1α/β KO mice, IL-1α/β KO BM cell co-cultures failed to undergo efficient osteoclast-like multinucleated cell (OCL) differentiation, although high levels of receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) was induced. In contrast, efficient OCL differentiation was observed in IL-1α/β KO osteoblast/WT BM cell co-cultures, in which high levels of IL-1α/β and low levels of RANKL were produced. Addition of IL-1α to IL-1α/β KO BM-derived macrophage cultures markedly enhanced OCL differentiation induced by soluble RANKL, and the downstream molecules of receptor activator of NF-κB (RANK) including c-Jun N-terminal factor, extracellular signal-regulated kinase and c-Fos were less activated in the absence of IL-1 upon treatment with RANKL. Taken together, these results indicate that IL-1 directly activates RANK signaling other than inducing RANKL to promote osteoclastogenesis and plays an important role in physiological bone metabolism.


Arthritis Research & Therapy | 2006

Identification of arthritis-related gene clusters by microarray analysis of two independent mouse models for rheumatoid arthritis

Noriyuki Fujikado; Shinobu Saijo; Yoichiro Iwakura

Rheumatoid arthritis (RA) is an autoimmune disease affecting approximately 1% of the population worldwide. Previously, we showed that human T-cell leukemia virus type I-transgenic mice and interleukin-1 receptor antagonist-knockout mice develop autoimmunity and joint-specific inflammation that resembles human RA. To identify genes involved in the pathogenesis of arthritis, we analyzed the gene expression profiles of these animal models by using high-density oligonucleotide arrays. We found 1,467 genes that were differentially expressed from the normal control mice by greater than threefold in one of these animal models. The gene expression profiles of the two models correlated well. We extracted 554 genes whose expression significantly changed in both models, assuming that pathogenically important genes at the effector phase would change in both models. Then, each of these commonly changed genes was mapped into the whole genome in a scale of the 1-megabase pairs. We found that the transcriptome map of these genes did not distribute evenly on the chromosome but formed clusters. These identified gene clusters include the major histocompatibility complex class I and class II genes, complement genes, and chemokine genes, which are well known to be involved in the pathogenesis of RA at the effector phase. The activation of these gene clusters suggests that antigen presentation and lymphocyte chemotaxisis are important for the development of arthritis. Moreover, by searching for such clusters, we could detect genes with marginal expression changes. These gene clusters include schlafen and membrane-spanning four-domains subfamily A genes whose function in arthritis has not yet been determined. Thus, by combining two etiologically different RA models, we succeeded in efficiently extracting genes functioning in the development of arthritis at the effector phase. Furthermore, we demonstrated that identification of gene clusters by transcriptome mapping is a useful way to find potentially pathogenic genes among genes whose expression change is only marginal.


Arthritis Research & Therapy | 2010

CXC chemokine receptor 4 expressed in T cells plays an important role in the development of collagen-induced arthritis

Soo-hyun Chung; Keisuke Seki; Byung-Il Choi; Keiko B. Kimura; Akihiko Ito; Noriyuki Fujikado; Shinobu Saijo; Yoichiro Iwakura

IntroductionChemokines and their receptors are potential therapeutic targets in rheumatoid arthritis (RA). Among these, several studies suggested the involvement of CXC chemokine 4 (CXCR4) and its ligand CXC ligand 12 (SDF-1) in RA pathogenesis. However, the role of these molecules in T-cell function is not known completely because of embryonic lethality of Cxcr4- and Cxcl12-deficient mice. In this report, we generated T cell-specific Cxcr4-deficient mice and showed that the CXCR4 in T cells is important for the development of collagen-induced arthritis (CIA).MethodsT cell-specific Cxcr4-deficient mice were generated by using the Cre-loxP system. Mice harboring loxP sites flanking exon 2 of the Cxcr4gene (Cxcr4flox/flox ) were generated by homologous recombination and crossed with Cre transgenic mice expressing Cre recombinase under the control of Lck promoter (Cxcr4+/+ /Lck-Cremice) to generate T cell-specific Cxcr4-deficient mice (Cxcr4flox/flox /Lck-Cre mice). CIA was induced by immunization with chicken type II collagen and Complete Freunds Adjuvant (CFA).ResultsThe incidence, but not the severity, of CIA was significantly reduced in Cxcr4flox/flox /Lck-Cre mice compared with Cxcr4+/+/Lck-Cre mice. We found that the expression of CXCR4 was enhanced in activated T cells, and the migration of Cxcr4-deficient T cells toward SDF-1 was severely impaired. However, antibody production, cellular proliferative response, and cytokine production on treatment with type II collagen (IIC) were normal in these knockout mice, suggesting that CXCR4 is not involved in T-helper functions. Interestingly, the proportion of CXCR4-expressing T cells was much increased in affected joints compared with that in draining lymph nodes in CIA-induced mice, and distribution of Cxcr4flox/flox /Lck-Cre mouse-derived T cells into affected joints was suppressed compared with that in Cxcr4+/+/Lck-Cre T cells.ConclusionsThese results indicate that CXCR4 expression in T cells is important for the development of CIA, by recruiting activated T cells toward inflammatory sites, and suggest that CXCR4 is a good target for the treatment of RA in humans.


Journal of Immunology | 2015

DCIR Maintains Bone Homeostasis by Regulating IFN-γ Production in T Cells

Takumi Maruhashi; Tomonori Kaifu; Rikio Yabe; Akimasa Seno; Soo Hyun Chung; Noriyuki Fujikado; Yoichiro Iwakura

Dendritic cell immunoreceptor (DCIR) is a C-type lectin receptor mainly expressed in DCs. Dcir−/− mice spontaneously develop autoimmune enthesitis and ankylosis accompanied by fibrocartilage proliferation and ectopic ossification. However, the mechanisms of new bone/cartilage formation in Dcir−/− mice remain to be elucidated. In this study, we show that DCIR maintains bone homeostasis by regulating IFN-γ production under pathophysiological conditions. DCIR deficiency increased bone volume in femurs and caused aberrant ossification in joints, whereas these symptoms were abolished in Rag2−/−Dcir−/− mice. IFN-γ–producing T cells accumulated in lymph nodes and joints of Dcir−/− mice, and purified Dcir−/− DCs enhanced IFN-γ+ T cell differentiation. The ankylotic changes and bone volume increase were suppressed in the absence of IFN-γ. Thus, IFN-γ is a positive chondrogenic and osteoblastogenic factor, and DCIR is a crucial regulator of bone metabolism; consequently, both factors are potential targets for therapies directed against bone metabolic diseases.


Nature Immunology | 2007

Dectin-1 is required for host defense against Pneumocystis carinii but not against Candida albicans

Shinobu Saijo; Noriyuki Fujikado; Takahisa Furuta; Soo-hyun Chung; Hayato Kotaki; Keisuke Seki; Katsuko Sudo; Shizuo Akira; Yoshiyuki Adachi; Naohito Ohno; Takeshi Kinjo; Kiwamu Nakamura; Kazuyoshi Kawakami; Yoichiro Iwakura


Immunity | 2016

Aire Inhibits the Generation of a Perinatal Population of Interleukin-17A-Producing γδ T Cells to Promote Immunologic Tolerance

Noriyuki Fujikado; Alexander O. Mann; Kushagra Bansal; Kimberly R. Romito; Elise M.N. Ferre; Sergio D. Rosenzweig; Michail S. Lionakis; Christophe Benoist; Diane Mathis

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Yoichiro Iwakura

Tokyo University of Science

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Tomonori Kaifu

Tokyo University of Science

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Katsuko Sudo

Tokyo Medical University

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