Papers - Yoshimura, Akihiko

SOCS1 and regulation of regulatory T cells plasticity

Takahashi Reiko, Yoshimura Akihiko

Journal of immunology research 2014   943149 2014

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<p>Several reports have suggested that natural regulatory T cells (Tregs) lose Forkhead box P3 (Foxp3) expression and suppression activity under certain inflammatory conditions. Treg plasticity has been studied because it may be associated with the pathogenesis of autoimmunity. Some studies showed that a minor uncommitted Foxp3(+) T cell population, which lacks hypomethylation at Treg-specific demethylation regions (TSDRs), may convert to effector/helper T cells. Suppressor of cytokine signaling 1 (SOCS1), a negative regulator of cytokine signaling, has been reported to play an important role in Treg cell integrity and function by protecting the cells from excessive inflammatory cytokines. In this review, we discuss Treg plasticity and maintenance of suppression functions in both physiological and pathological settings. In addition, we discuss molecular mechanisms of maintaining Treg plasticity by SOCS1 and other molecules. Such information will be useful for therapy of autoimmune diseases and reinforcement of antitumor immunity. </p>

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Role of inflammatory cytokines in brain ischemia

Yoshimura Akihiko

Therapeutic Research 35 ( 9 ) 801 - 803 2014

ISSN  0289-8020

Regulation of human autoimmune regulator (AIRE) gene translation by miR-220b

Matsuo Tomohito, Noguchi Yukiko, Shindo Mieko, Morita Yoshifumi, Oda Yoshie, Yoshida Eiko, Hamada Hiroko, Harada Mine, Shiokawa Yuichi, Nishida Takahiro, Tominaga Ryuji, Kikushige Yoshikane, Akashi Koichi, Kudoh Jun, Shimizu Nobuyoshi, Tanaka Yuka, Umemura Tsukuru, Taniguchi Taketoshi, Yoshimura Akihiko, Kobayashi Takashi, Mitsuyama Masao, Kurisaki Hironori, Katsuta Hitoshi, Nagafuchi Seiho

Gene 530 ( 1 ) 19 - 25 2013.11

ISSN  0378-1119

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<p>Although mutations of autoimmune regulator (AIRE) gene are responsible for autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), presenting a wide spectrum of many characteristic and non-characteristic clinical features, some patients lack AIRE gene mutations. Therefore, something other than a mutation, such as dysregulation of AIRE gene, may be a causal factor for APECED or its related diseases. However, regulatory mechanisms for AIRE gene expression and/or translation have still remained elusive. We found that IL-2-stimulated CD4⁺ T (IL-2T) cells showed a high expression of AIRE gene, but very low AIRE protein production, while Epstein-Barr virus-transformed B (EBV-B) cells express both AIRE gene and AIRE protein. By using microarray analysis, we could identify miR-220b as a possible regulatory mechanism for AIRE gene translation in IL-2T cells. Here we report that miR-220b significantly reduced the expression of AIRE protein in AIRE gene with 3'UTR region transfected 293T cells, whereas no alteration of AIRE protein production was observed in the open reading frame of AIRE gene alone transfected cells. In addition, anti-miR-220b reversed the inhibitory function of miR-220b for the expression of AIRE protein in AIRE gene with 3'UTR region transfected cells. Moreover, when AIRE gene transfected cells with mutated 3'UTR were transfected with miR-220b, no reduction of AIRE protein production was observed. Taken together, it was concluded that miR-220b inhibited the AIRE gene translation through the 3'UTR region of AIRE gene, indicating that miR-220b could serve as a regulator for human AIRE gene translation. © 2013 Elsevier B.V.</p>

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Regulation of human autoimmune regulator (AIRE) gene translation by miR-220b

Matsuo Tomohito, Noguchi Yukiko, Shindo Mieko, Morita Yoshifumi, Oda Yoshie, Yoshida Eiko, Hamada Hiroko, Harada Mine, Shiokawa Yuichi, Nishida Takahiro, Tominaga Ryuji, Kikushige Yoshikane, Akashi Koichi, Kudoh Jun, Shimizu Nobuyoshi, Tanaka Yuka, Umemura Tsukuru, Taniguchi Taketoshi, Yoshimura Akihiko, Kobayashi Takashi, Mitsuyama Masao, Kurisaki Hironori, Katsuta Hitoshi, Nagafuchi Seiho

Gene 530 ( 1 ) 19 - 25 2013.11

ISSN  0378-1119

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<p>Although mutations of autoimmune regulator (AIRE) gene are responsible for autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), presenting a wide spectrum of many characteristic and non-characteristic clinical features, some patients lack AIRE gene mutations. Therefore, something other than a mutation, such as dysregulation of AIRE gene, may be a causal factor for APECED or its related diseases. However, regulatory mechanisms for AIRE gene expression and/or translation have still remained elusive. We found that IL-2-stimulated CD4⁺ T (IL-2T) cells showed a high expression of AIRE gene, but very low AIRE protein production, while Epstein-Barr virus-transformed B (EBV-B) cells express both AIRE gene and AIRE protein. By using microarray analysis, we could identify miR-220b as a possible regulatory mechanism for AIRE gene translation in IL-2T cells. Here we report that miR-220b significantly reduced the expression of AIRE protein in AIRE gene with 3'UTR region transfected 293T cells, whereas no alteration of AIRE protein production was observed in the open reading frame of AIRE gene alone transfected cells. In addition, anti-miR-220b reversed the inhibitory function of miR-220b for the expression of AIRE protein in AIRE gene with 3'UTR region transfected cells. Moreover, when AIRE gene transfected cells with mutated 3'UTR were transfected with miR-220b, no reduction of AIRE protein production was observed. Taken together, it was concluded that miR-220b inhibited the AIRE gene translation through the 3'UTR region of AIRE gene, indicating that miR-220b could serve as a regulator for human AIRE gene translation. © 2013 Elsevier B.V.</p>

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IL-23 protection against Plasmodium berghei infection in mice is partially dependent on IL-17 from macrophages

Ishida Hidekazu, Imai Takashi, Suzue Kazutomo, Hirai Makoto, Taniguchi Tomoyo, Yoshimura Akihiko, Iwakura Yoichiro, Okada Hiroko, Suzuki Tomohisa, Shimokawa Chikako, Hisaeda Hajime

European Journal of Immunology 43 ( 10 ) 2696 - 2706 2013.10

ISSN  0014-2980

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<p>Although IL-12 is believed to contribute to protective immune responses, the role played by IL-23 (a member of the IL-12 family) in malaria is elusive. Here, we show that IL-23 is produced during infection with Plasmodium berghei NK65. Mice deficient in IL-23 (p19KO) had higher parasitemia and died earlier than wild-type (WT) controls. Interestingly, p19KO mice had lower numbers of IL-17-producing splenic cells than their WT counterparts. Furthermore, mice deficient in IL-17 (17KO) suffered higher parasitemia than the WT controls, indicating that IL-23-mediated protection is dependent on induction of IL-17 during infection. We found that macrophages were responsible for IL-17 production in response to IL-23. We observed a striking reduction in splenic macrophages in the p19KO and 17KO mice, both of which became highly susceptible to infection. Thus, IL-17 appears to be crucial for maintenance of splenic macrophages. Adoptive transfer of macrophages into macrophage-depleted mice confirmed that macrophage-derived IL-17 is required for macrophage accumulation and parasite eradication in the recipient mice. We also found that IL-17 induces CCL2/7, which recruit macrophages. Our findings reveal a novel protective mechanism whereby IL-23, IL-17, and macrophages reduce the severity of infection with blood-stage malaria parasites. © 2013 WILEY-VCH Verlag GmbH &amp; Co. KGaA, Weinheim.</p>

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IL-23 protection against Plasmodium berghei infection in mice is partially dependent on IL-17 from macrophages

Ishida Hidekazu, Imai Takashi, Suzue Kazutomo, Hirai Makoto, Taniguchi Tomoyo, Yoshimura Akihiko, Iwakura Yoichiro, Okada Hiroko, Suzuki Tomohisa, Shimokawa Chikako, Hisaeda Hajime

European Journal of Immunology 43 ( 10 ) 2696 - 2706 2013.10

ISSN  0014-2980

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<p>Although IL-12 is believed to contribute to protective immune responses, the role played by IL-23 (a member of the IL-12 family) in malaria is elusive. Here, we show that IL-23 is produced during infection with Plasmodium berghei NK65. Mice deficient in IL-23 (p19KO) had higher parasitemia and died earlier than wild-type (WT) controls. Interestingly, p19KO mice had lower numbers of IL-17-producing splenic cells than their WT counterparts. Furthermore, mice deficient in IL-17 (17KO) suffered higher parasitemia than the WT controls, indicating that IL-23-mediated protection is dependent on induction of IL-17 during infection. We found that macrophages were responsible for IL-17 production in response to IL-23. We observed a striking reduction in splenic macrophages in the p19KO and 17KO mice, both of which became highly susceptible to infection. Thus, IL-17 appears to be crucial for maintenance of splenic macrophages. Adoptive transfer of macrophages into macrophage-depleted mice confirmed that macrophage-derived IL-17 is required for macrophage accumulation and parasite eradication in the recipient mice. We also found that IL-17 induces CCL2/7, which recruit macrophages. Our findings reveal a novel protective mechanism whereby IL-23, IL-17, and macrophages reduce the severity of infection with blood-stage malaria parasites. © 2013 WILEY-VCH Verlag GmbH &amp; Co. KGaA, Weinheim.</p>

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Th17 cells carrying TCR recognizing epidermal autoantigen induce psoriasis-like skin inflammation

Nishimoto Shuhei, Kotani Hitoshi, Tsuruta Sanae, Shimizu Nana, Ito Minako, Shichita Takashi, Morita Rimpei, Takahashi Hayato, Amagai Masayuki, Yoshimura Akihiko

Journal of Immunology 191 ( 6 ) 3065 - 3072 2013.09

ISSN  0022-1767

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<p>Psoriasis is considered a Th17-type autoimmune skin inflammatory disease; however, involvement of an autoantigen-specific TCR has not been established. In this study, we show that psoriasis-like skin inflammation can be induced by autoreactive Th17 cells.We previously developed the desmoglein 3-specific TCR-transgenic (Dsg3H1) mouse, in which CD4+ T cells recognize physiological epidermal autoantigen. T cells from Dsg3H1 mice were polarized into Th17 cells in vitro and then adoptively transferred into Rag2^-/- mice. Dsg3H1-Th17 cells induced severe psoriasis-like skin inflammation within 2 wk after transfer in the tissues in which desmoglein 3 is expressed. Such pathology was not observed when wild-type Th17 cells or Th1-skewed Dsg3H1 T cells were transferred, and it was strongly suppressed by anti-IL-12/23 and anti-IL-17 Abs. Although IFN-γ⁺/IL-17⁺ T cells accumulated in the skin lesions of mice that received Dsg3H1-Th17 cells, IFN-γ-deficient Dsg3H1-Th17 cells were fully pathogenic. These results demonstrate that cutaneous psoriasis-like immunopathology can be developed by epidermis-specific recognition of Th17 cells, which is strictly dependent on IL-17 but not IFN-γ. Copyright © 2013 by The American Association of Immunologists, Inc.</p>

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Th17 cells carrying TCR recognizing epidermal autoantigen induce psoriasis-like skin inflammation

Nishimoto Shuhei, Kotani Hitoshi, Tsuruta Sanae, Shimizu Nana, Ito Minako, Shichita Takashi, Morita Rimpei, Takahashi Hayato, Amagai Masayuki, Yoshimura Akihiko

Journal of Immunology 191 ( 6 ) 3065 - 3072 2013.09

ISSN  0022-1767

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<p>Psoriasis is considered a Th17-type autoimmune skin inflammatory disease; however, involvement of an autoantigen-specific TCR has not been established. In this study, we show that psoriasis-like skin inflammation can be induced by autoreactive Th17 cells.We previously developed the desmoglein 3-specific TCR-transgenic (Dsg3H1) mouse, in which CD4+ T cells recognize physiological epidermal autoantigen. T cells from Dsg3H1 mice were polarized into Th17 cells in vitro and then adoptively transferred into Rag2^-/- mice. Dsg3H1-Th17 cells induced severe psoriasis-like skin inflammation within 2 wk after transfer in the tissues in which desmoglein 3 is expressed. Such pathology was not observed when wild-type Th17 cells or Th1-skewed Dsg3H1 T cells were transferred, and it was strongly suppressed by anti-IL-12/23 and anti-IL-17 Abs. Although IFN-γ⁺/IL-17⁺ T cells accumulated in the skin lesions of mice that received Dsg3H1-Th17 cells, IFN-γ-deficient Dsg3H1-Th17 cells were fully pathogenic. These results demonstrate that cutaneous psoriasis-like immunopathology can be developed by epidermis-specific recognition of Th17 cells, which is strictly dependent on IL-17 but not IFN-γ. Copyright © 2013 by The American Association of Immunologists, Inc.</p>

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TRAF6 Is Essential for Maintenance of Regulatory T Cells That Suppress Th2 Type Autoimmunity

Muto Go, Kotani Hitoshi, Kondo Taisuke, Morita Rimpei, Tsuruta Sanae, Kobayashi Takashi, Luche Hervé, Fehling Hans Joerg, Walsh Matthew, Choi Yongwon, Yoshimura Akihiko

PLoS ONE 8 ( 9 )  2013.09

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<p>Regulatory T cells (Tregs) maintain immune homeostasis by limiting inflammatory responses. TRAF6 plays a key role in the regulation of innate and adaptive immunity by mediating signals from various receptors including the T-cell receptor (TCR). T cell-specific deletion of TRAF6 has been shown to induce multiorgan inflammatory disease, but the role of TRAF6 in Tregs remains to be investigated. Here, we generated Treg-specific TRAF6-deficient mice using Foxp3-Cre and TRAF6-flox mice. Treg-specific TRAF6-deficient (cKO) mice developed allergic skin diseases, arthritis, lymphadenopathy and hyper IgE phenotypes. Although TRAF6-deficient Tregs possess similar in vitro suppression activity compared to wild-type Tregs, TRAF6-deficient Tregs did not suppress colitis in lymphopenic mice very efficiently due to reduced number of Foxp3-positive cells. In addition, the fraction of TRAF6-deficient Tregs was reduced compared with wild-type Tregs in female cKO mice without inflammation. Moreover, adoptive transfer of Foxp3 ⁺ Tregs into Rag2^-/- mice revealed that TRAF6-deficient Tregs converted into Foxp3^- cells more rapidly than WT Tregs under lymphopenic conditions. Fate-mapping analysis also revealed that conversion of Tregs from Foxp3⁺ to Foxp3^- (exFoxp3 cells) was accelerated in TRAF6-deficient Tregs. These data indicate that TRAF6 in Tregs plays important roles in the maintenance of Foxp3 in Tregs and in the suppression of pathogenic Th2 type conversion of Tregs. © 2013 Muto et al.</p>

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TRAF6 Is Essential for Maintenance of Regulatory T Cells That Suppress Th2 Type Autoimmunity

Muto Go, Kotani Hitoshi, Kondo Taisuke, Morita Rimpei, Tsuruta Sanae, Kobayashi Takashi, Luche Hervé, Fehling Hans Joerg, Walsh Matthew, Choi Yongwon, Yoshimura Akihiko

PLoS ONE 8 ( 9 )  2013.09

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<p>Regulatory T cells (Tregs) maintain immune homeostasis by limiting inflammatory responses. TRAF6 plays a key role in the regulation of innate and adaptive immunity by mediating signals from various receptors including the T-cell receptor (TCR). T cell-specific deletion of TRAF6 has been shown to induce multiorgan inflammatory disease, but the role of TRAF6 in Tregs remains to be investigated. Here, we generated Treg-specific TRAF6-deficient mice using Foxp3-Cre and TRAF6-flox mice. Treg-specific TRAF6-deficient (cKO) mice developed allergic skin diseases, arthritis, lymphadenopathy and hyper IgE phenotypes. Although TRAF6-deficient Tregs possess similar in vitro suppression activity compared to wild-type Tregs, TRAF6-deficient Tregs did not suppress colitis in lymphopenic mice very efficiently due to reduced number of Foxp3-positive cells. In addition, the fraction of TRAF6-deficient Tregs was reduced compared with wild-type Tregs in female cKO mice without inflammation. Moreover, adoptive transfer of Foxp3 ⁺ Tregs into Rag2^-/- mice revealed that TRAF6-deficient Tregs converted into Foxp3^- cells more rapidly than WT Tregs under lymphopenic conditions. Fate-mapping analysis also revealed that conversion of Tregs from Foxp3⁺ to Foxp3^- (exFoxp3 cells) was accelerated in TRAF6-deficient Tregs. These data indicate that TRAF6 in Tregs plays important roles in the maintenance of Foxp3 in Tregs and in the suppression of pathogenic Th2 type conversion of Tregs. © 2013 Muto et al.</p>

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Smad2/3 and IRF4 play a cooperative role in IL-9-producing T cell induction

Tamiya Taiga, Ichiyama Kenji, Kotani Hitoshi, Fukaya Tomohiro, Sekiya Takashi, Shichita Takashi, Honma Kiri, Yui Katsuyuki, Matsuyama Toshifumi, Nakao Takako, Fukuyama Satoru, Inoue Hiromasa, Nomura Masatoshi, Yoshimura Akihiko

Journal of Immunology 191 ( 5 ) 2360 - 2371 2013.09

ISSN  0022-1767

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<p>IL-9 is a pleiotropic cytokine that can regulate autoimmune and allergic responses. Th9 cells can develop from naive T cells or Th2 cells through stimulation by TGF-β in vitro. In this study, we demonstrated that Smad2 and Smad3 are necessary for IL-9 production from T cells in an OVA-induced asthma model using T cell-specific Smad2- and Smad3-deficient mice. Smad2 and Smad3 were also redundantly essential for TGF-β signaling to induce histone modifications for Il9 transcription. Although Smad2/3 was recruited to the Il9 promoter by TGF-β stimulation, they are not sufficient to activate the Il9 promoter. By the screening the transcription factors, we found that IFN regulatory factor 4 (IRF4) was essential for the Smad2/3-mediated Il9 promoter activation. In addition, Smad2/3 physically interacted with IRF4, and Smad2/3 did not bind to the Il9 promoter and could not induce Th9 in IRF4-deficient T cells. Similarly, IRF4 could not stimulate Il9 transcription in the absence of Smad2/3, and TGF-β enhanced IRF4 recruitment to the Il9 promoter in a Smad2/3-dependent manner. We propose that Smad2/3 and IRF4 cooperatively transactivate the Il9 promoter and play an important role in regulating allergic immune responses by inducing Th9 cells. Copyright © 2013 by The American Association of Immunologists, Inc.</p>

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Smad2/3 and IRF4 play a cooperative role in IL-9-producing T cell induction

Tamiya Taiga, Ichiyama Kenji, Kotani Hitoshi, Fukaya Tomohiro, Sekiya Takashi, Shichita Takashi, Honma Kiri, Yui Katsuyuki, Matsuyama Toshifumi, Nakao Takako, Fukuyama Satoru, Inoue Hiromasa, Nomura Masatoshi, Yoshimura Akihiko

Journal of Immunology 191 ( 5 ) 2360 - 2371 2013.09

ISSN  0022-1767

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<p>IL-9 is a pleiotropic cytokine that can regulate autoimmune and allergic responses. Th9 cells can develop from naive T cells or Th2 cells through stimulation by TGF-β in vitro. In this study, we demonstrated that Smad2 and Smad3 are necessary for IL-9 production from T cells in an OVA-induced asthma model using T cell-specific Smad2- and Smad3-deficient mice. Smad2 and Smad3 were also redundantly essential for TGF-β signaling to induce histone modifications for Il9 transcription. Although Smad2/3 was recruited to the Il9 promoter by TGF-β stimulation, they are not sufficient to activate the Il9 promoter. By the screening the transcription factors, we found that IFN regulatory factor 4 (IRF4) was essential for the Smad2/3-mediated Il9 promoter activation. In addition, Smad2/3 physically interacted with IRF4, and Smad2/3 did not bind to the Il9 promoter and could not induce Th9 in IRF4-deficient T cells. Similarly, IRF4 could not stimulate Il9 transcription in the absence of Smad2/3, and TGF-β enhanced IRF4 recruitment to the Il9 promoter in a Smad2/3-dependent manner. We propose that Smad2/3 and IRF4 cooperatively transactivate the Il9 promoter and play an important role in regulating allergic immune responses by inducing Th9 cells. Copyright © 2013 by The American Association of Immunologists, Inc.</p>

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[Post-ischemic innate immunity and its application for novel therapeutic strategy targeting brain inflammation].

Ito Minako, Kondo Taisuke, Shichita Takashi, Yoshimura Akihiko

Nihon rinsho. Japanese journal of clinical medicine 71 ( 7 ) 1291 - 1301 2013.07

ISSN  0047-1852

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<p>Stroke or brain ischemia is one of the major causes of death and disability worldwide. Post-ischemic inflammation is an essential step in the progression of brain ischemia-reperfusion injury. In a mouse stroke model, we have reported that IL-23 produced from infiltrating macrophages induces IL-17 producing T cells. IL-17 is mainly produced from gammadeltaT cells and promotes delayed (day 3-4) ischemic brain damage. We also demonstrated that peroxiredoxin (Prx) family proteins released extracellularly from necrotic brain cells induce expression of inflammatory cytokines including IL-23 in macrophages through activation of Toll-like receptor 2(TLR2) and TLR4, thereby promoting neural cell death. We thus propose that regulation of the IL-23-IL-17 axis including gammadeltaT cells, macrophages, and extracellular Prxs could be a potent neuroprotective tool.</p>

CIS

Yoshimura Akihiko

Nature Immunology 14 ( 7 ) 692 - 694 2013.07

ISSN  1529-2908

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Critical and Independent Role for SOCS3 in Either Myeloid or T Cells in Resistance to Mycobacterium tuberculosis

Carow Berit, Reuschl Ann Kathrin, Gavier-Widén Dolores, Jenkins Brendan J., Ernst Matthias, Yoshimura Akihiko, Chambers Benedict J., Rottenberg Martin E.

PLoS Pathogens 9 ( 7 )  2013.07

ISSN  1553-7366

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<p>Suppressor of cytokine signalling 3 (SOCS3) negatively regulates STAT3 activation in response to several cytokines such as those in the gp130-containing IL-6 receptor family. Thus, SOCS3 may play a major role in immune responses to pathogens. In the present study, the role of SOCS3 in M. tuberculosis infection was examined. All Socs3^fl/fl LysM cre, Socs3^fl/fl lck cre (with SOCS3-deficient myeloid and lymphoid cells, respectively) and gp130^F/F mice, with a mutation in gp130 that impedes binding to SOCS3, showed increased susceptibility to infection with M. tuberculosis. SOCS3 binding to gp130 in myeloid cells conveyed resistance to M. tuberculosis infection via the regulation of IL-6/STAT3 signalling. SOCS3 was redundant for mycobacterial control by macrophages in vitro. Instead, SOCS3 expression in infected macrophages and DCs prevented the IL-6-mediated inhibition of TNF and IL-12 secretion and contributed to a timely CD4+ cell-dependent IFN-γ expression in vivo. In T cells, SOCS3 expression was essential for a gp130-independent control of infection with M. tuberculosis, but was neither required for the control of infection with attenuated M. bovis BCG nor for M. tuberculosis in BCG-vaccinated mice. Socs3^fl/fl lck cre mice showed an increased frequency of γδ+ T cells in different organs and an enhanced secretion of IL-17 by γδ+ T cells in response to infection. Socs3^fl/fl lck cre γδ+ T cells impaired the control of infection with M. tuberculosis. Thus, SOCS3 expression in either lymphoid or myeloid cells is essential for resistance against M. tuberculosis via discrete mechanisms. © 2013 Carow et al.</p>

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[Post-ischemic innate immunity and its application for novel therapeutic strategy targeting brain inflammation].

Ito Minako, Kondo Taisuke, Shichita Takashi, Yoshimura Akihiko

Nihon rinsho. Japanese journal of clinical medicine 71 ( 7 ) 1291 - 1301 2013.07

ISSN  0047-1852

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<p>Stroke or brain ischemia is one of the major causes of death and disability worldwide. Post-ischemic inflammation is an essential step in the progression of brain ischemia-reperfusion injury. In a mouse stroke model, we have reported that IL-23 produced from infiltrating macrophages induces IL-17 producing T cells. IL-17 is mainly produced from gammadeltaT cells and promotes delayed (day 3-4) ischemic brain damage. We also demonstrated that peroxiredoxin (Prx) family proteins released extracellularly from necrotic brain cells induce expression of inflammatory cytokines including IL-23 in macrophages through activation of Toll-like receptor 2(TLR2) and TLR4, thereby promoting neural cell death. We thus propose that regulation of the IL-23-IL-17 axis including gammadeltaT cells, macrophages, and extracellular Prxs could be a potent neuroprotective tool.</p>

CIS

Yoshimura Akihiko

Nature Immunology 14 ( 7 ) 692 - 694 2013.07

ISSN  1529-2908

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Critical and Independent Role for SOCS3 in Either Myeloid or T Cells in Resistance to Mycobacterium tuberculosis

Carow Berit, Reuschl Ann Kathrin, Gavier-Widén Dolores, Jenkins Brendan J., Ernst Matthias, Yoshimura Akihiko, Chambers Benedict J., Rottenberg Martin E.

PLoS Pathogens 9 ( 7 )  2013.07

ISSN  1553-7366

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<p>Suppressor of cytokine signalling 3 (SOCS3) negatively regulates STAT3 activation in response to several cytokines such as those in the gp130-containing IL-6 receptor family. Thus, SOCS3 may play a major role in immune responses to pathogens. In the present study, the role of SOCS3 in M. tuberculosis infection was examined. All Socs3^fl/fl LysM cre, Socs3^fl/fl lck cre (with SOCS3-deficient myeloid and lymphoid cells, respectively) and gp130^F/F mice, with a mutation in gp130 that impedes binding to SOCS3, showed increased susceptibility to infection with M. tuberculosis. SOCS3 binding to gp130 in myeloid cells conveyed resistance to M. tuberculosis infection via the regulation of IL-6/STAT3 signalling. SOCS3 was redundant for mycobacterial control by macrophages in vitro. Instead, SOCS3 expression in infected macrophages and DCs prevented the IL-6-mediated inhibition of TNF and IL-12 secretion and contributed to a timely CD4+ cell-dependent IFN-γ expression in vivo. In T cells, SOCS3 expression was essential for a gp130-independent control of infection with M. tuberculosis, but was neither required for the control of infection with attenuated M. bovis BCG nor for M. tuberculosis in BCG-vaccinated mice. Socs3^fl/fl lck cre mice showed an increased frequency of γδ+ T cells in different organs and an enhanced secretion of IL-17 by γδ+ T cells in response to infection. Socs3^fl/fl lck cre γδ+ T cells impaired the control of infection with M. tuberculosis. Thus, SOCS3 expression in either lymphoid or myeloid cells is essential for resistance against M. tuberculosis via discrete mechanisms. © 2013 Carow et al.</p>

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A single strain of Clostridium butyricum induces intestinal IL-10-producing macrophages to suppress acute experimental colitis in mice

Hayashi Atsushi, Sato Toshiro, Kamada Nobuhiko, Mikami Yohei, Matsuoka Katsuyoshi, Hisamatsu Tadakazu, Hibi Toshifumi, Roers Axel, Yagita Hideo, Ohteki Toshiaki, Yoshimura Akihiko, Kanai Takanori

Cell Host and Microbe 13 ( 6 ) 711 - 722 2013.06

ISSN  1931-3128

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<p>Imbalance in gut bacterial composition provokes host proinflammatory responses causing diseases such as colitis. Colonization with a mixture of Clostridium species from clusters IV and XIVa was shown to suppress colitis through the induction of IL-10-producing regulatory T (Treg) cells. We demonstrate that a distinct Clostridium strain from cluster I, Clostridium butyricum (CB), prevents acute experimental colitis in mice through induction of IL-10, an anti-inflammatory cytokine. However, while CB treatment had no effect on IL-10 production by T cells, IL-10-producing F4/80⁺CD11b ⁺CD11c^int macrophages accumulated in the inflamed mucosa after CB treatment. CB directly triggered IL-10 production by intestinal macrophages in inflamed mucosa via the TLR2/MyD88 pathway. The colitis-preventing effect of CB was negated in macrophage-specific IL-10-deficient mice, suggesting that induction of IL-10 by intestinal macrophages is crucial for the probiotic action of CB. Collectively, CB promotes IL-10 production by intestinal macrophages in inflamed mucosa, thereby preventing experimental colitis in mice. © 2013 Elsevier Inc.</p>

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A single strain of Clostridium butyricum induces intestinal IL-10-producing macrophages to suppress acute experimental colitis in mice

Hayashi Atsushi, Sato Toshiro, Kamada Nobuhiko, Mikami Yohei, Matsuoka Katsuyoshi, Hisamatsu Tadakazu, Hibi Toshifumi, Roers Axel, Yagita Hideo, Ohteki Toshiaki, Yoshimura Akihiko, Kanai Takanori

Cell Host and Microbe 13 ( 6 ) 711 - 722 2013.06

ISSN  1931-3128

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<p>Imbalance in gut bacterial composition provokes host proinflammatory responses causing diseases such as colitis. Colonization with a mixture of Clostridium species from clusters IV and XIVa was shown to suppress colitis through the induction of IL-10-producing regulatory T (Treg) cells. We demonstrate that a distinct Clostridium strain from cluster I, Clostridium butyricum (CB), prevents acute experimental colitis in mice through induction of IL-10, an anti-inflammatory cytokine. However, while CB treatment had no effect on IL-10 production by T cells, IL-10-producing F4/80⁺CD11b ⁺CD11c^int macrophages accumulated in the inflamed mucosa after CB treatment. CB directly triggered IL-10 production by intestinal macrophages in inflamed mucosa via the TLR2/MyD88 pathway. The colitis-preventing effect of CB was negated in macrophage-specific IL-10-deficient mice, suggesting that induction of IL-10 by intestinal macrophages is crucial for the probiotic action of CB. Collectively, CB promotes IL-10 production by intestinal macrophages in inflamed mucosa, thereby preventing experimental colitis in mice. © 2013 Elsevier Inc.</p>

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