Aoi Akitsu
University of Tokyo
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Featured researches published by Aoi Akitsu.
Immunity | 2009
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
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 Communications | 2015
Aoi Akitsu; Harumichi Ishigame; Shigeru Kakuta; Soo Hyun Chung; Satoshi Ikeda; Kenji Shimizu; Sachiko Kubo; Yang Liu; Masayuki Umemura; Goro Matsuzaki; Yasunobu Yoshikai; Shinobu Saijo; Yoichiro Iwakura
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 Immunology | 2016
Bradley N. Martin; Chenhui Wang; Cun Jin Zhang; Zizhen Kang; Muhammet Fatih Gulen; Jarod A. Zepp; Junjie Zhao; Guanglin Bian; Jeong Su Do; Booki Min; Paul G. Pavicic; Caroline El-Sanadi; Paul L. Fox; Aoi Akitsu; Yoichiro Iwakura; Anasuya Sarkar; Mark D. Wewers; William J. Kaiser; Edward S. Mocarski; Marc E. Rothenberg; Amy G. Hise; George R. Dubyak; Richard M. Ransohoff; Xiaoxia Li
Interleukin 1β (IL-1β) is critical for the in vivo survival, expansion and effector function of IL-17–producing helper T (TH17) cells during autoimmune responses, including experimental autoimmune encephalomyelitis (EAE). However, the spatiotemporal role and cellular source of IL-1β during EAE pathogenesis are poorly defined. In the present study, we uncovered a T cell–intrinsic inflammasome that drives IL-1β production during TH17-mediated EAE pathogenesis. Activation of T cell antigen receptors induced expression of pro-IL-1β, whereas ATP stimulation triggered T cell production of IL-1β via ASC-NLRP3–dependent caspase-8 activation. IL-1R was detected on TH17 cells but not on type 1 helper T (TH1) cells, and ATP-treated TH17 cells showed enhanced survival compared with ATP-treated TH1 cells, suggesting autocrine action of TH17-derived IL-1β. Together these data reveal a critical role for IL-1β produced by a TH17 cell–intrinsic ASC–NLRP3–caspase-8 inflammasome during inflammation of the central nervous system.
Journal of Immunology | 2014
Satoshi Ikeda; Shinobu Saijo; Masanori A. Murayama; Kenji Shimizu; Aoi Akitsu; Yoichiro Iwakura
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.
Biochimica et Biophysica Acta | 2010
Kuniko Akama; Tomoe Horikoshi; Atsushi Sugiyama; Satoko Nakahata; Aoi Akitsu; Nobuyoshi Niwa; Atsushi Intoh; Yasutaka Kakui; Michiko Sugaya; Kazuo Takei; Noriaki Imaizumi; Takaya Sato; Rena Matsumoto; Hitoshi Iwahashi; Shin-ichi Kashiwabara; Tadashi Baba; Megumi Nakamura; Tosifusa Toda
In mammalian spermiogenesis, sperm mature during epididymal transit to get fertility. The pig sharing many physiological similarities with humans is considered a promising animal model in medicine. We examined the expression profiles of proteins from boar epididymal caput, corpus, and cauda sperm by two-dimensional gel electrophoresis and peptide mass fingerprinting. Our results indicated that protein disulfide isomerase-P5 (PDI-P5) human homolog was down-regulated from the epididymal corpus to cauda sperm, in contrast to the constant expression of protein disulfide isomerase A3 (PDIA3) human homolog. To examine the functions of PDIA3 and PDI-P5, we cloned and sequenced cDNAs of pig PDIA3 and PDI-P5 protein precursors. Each recombinant pig mature PDIA3 and PDI-P5 expressed in Escherichia coli showed thiol-dependent disulfide reductase activities in insulin turbidity assay. Although PDIA3 showed chaperone activity to promote oxidative refolding of reduced denatured lysozyme, PDI-P5 exhibited anti-chaperone activity to inhibit oxidative refolding of lysozyme at an equimolar ratio. SDS-PAGE and Western blotting analysis suggested that disulfide cross-linked and non-productively folded lysozyme was responsible for the anti-chaperone activity of PDI-P5. These results provide a molecular basis and insights into the physiological roles of PDIA3 and PDI-P5 in sperm maturation and fertilization.
Biochemical and Biophysical Research Communications | 2014
Eri Shimura; Akiko Shibui; Seiko Narushima; Aya Nambu; Sachiko Yamaguchi; Aoi Akitsu; Warren J. Leonard; Yoichiro Iwakura; Kenji Matsumoto; Hajime Suto; Ko Okumura; Katsuko Sudo; Susumu Nakae
IL-17RA is a shared receptor subunit for several cytokines of the IL-17 family, including IL-17A, IL-17C, IL-17E (also called IL-25) and IL-17F. It has been shown that mice deficient in IL-17RA are more susceptible to sepsis than wild-type mice, suggesting that IL-17RA is important for host defense against sepsis. However, it is unclear which ligands for IL-17RA, such as IL-17A, IL-17C, IL-17E/IL-25 and/or IL-17F, are involved in the pathogenesis of sepsis. Therefore, we examined IL-17A, IL-17E/IL-25 and IL-17F for possible involvement in LPS-induced endotoxin shock. IL-17A-deficient mice, but not IL-25- or IL-17F-deficient mice, were resistant to LPS-induced endotoxin shock, as compared with wild-type mice. Nevertheless, studies using IL-6-deficient, IL-21Rα-deficient and Rag-2-deficient mice, revealed that neither IL-6 and IL-21, both of which are important for Th17 cell differentiation, nor Th17 cells were essential for the development of LPS-induced endotoxin shock, suggesting that IL-17A-producing cells other than Th17 cells were important in the setting. In this connection, IL-17A was produced by macrophages, DCs and eosinophils after LPS injection. Taken together, these findings indicate that IL-17A, but not IL-17F or IL-25, is crucial for LPS-induced endotoxin shock. In addition, macrophages, DCs and eosinophils, but not Th17 cells or γδ T cells, may be sources of IL-17A during LPS-induced endotoxin shock.
Experimental Animals | 2014
Aoi Akitsu; Shigeru Kakuta; Shinobu Saijo; Yoichiro Iwakura
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.
Arthritis Research & Therapy | 2012
Aoi Akitsu; Harumichi Ishigame; Shigeru Kakuta; Shinobu Saijo; Yoichiro Iwakura
BIO-PROTOCOL | 2016
Aoi Akitsu; Yoichiro Iwakura