Details of a Researcher - Mikami, Yohei

Papers - Mikami, Yohei

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Classical Th1 cells obtain colitogenicity by co-existence of RORgammat-expressing T cells in experimental colitis

Saigusa, K., Hisamatsu, T., Handa, T., Sujino, T., Mikami, Y., Hayashi, A., Mizuno, S., Takeshita, K., Sato, T., Matsuoka, K. and Kanai, T.

Inflamm Bowel Dis 20 ( 10 ) 1820 - 7 2014.10

ISSN 1078-0998

BACKGROUND: Both Th1 and Th17 cell types are involved in the pathogenesis of chronic intestinal inflammation. We recently demonstrated that retinoid-related orphan receptor gamma t (RORgammat)-expressing Th17 cells are progenitor cells for alternative Th1 cells, which have the potential to induce colitis. However, the involvement of classical Th1 (cTh1) cells generated directly from naive T cells without RORgammat expression in the pathogenesis of colitis remains poorly understood. METHODS: We performed a series of in vivo experiments using a murine chronic colitis model induced by adoptive transfer of splenic CD4CD45RB(high) T cells obtained from wild-type, RORgammat(gfp/gfp), or RORgammat(gfp/gfp) mice into RAG-2(-/-) mice. RESULTS: RAG-2(-/-) mice receiving transfer of in vitro-manipulated RORgammat(gfp/gfp) Th1 cells developed colitis. RAG-2(-/-) mice co-transferred with splenic CD4CD45RB(high) T cells obtained from wild-type mice and RORgammat(gfp/gfp) mice developed colitis with a significant increase in RORgammat cTh1 cell numbers when compared with noncolitic mice transferred with splenic CD4CD45RB(high) T cells obtained from RORgammat(gfp/gfp) mice. Furthermore, RAG-2(-/-) mice transferred with in vivo-manipulated RORgammat(gfp/gfp) cTh1 cells developed colitis with a significant increase in RORgammat(gfp/gfp) cTh1 cell numbers. CONCLUSIONS: These findings indicate that both alternative Th1 cells and cTh1 cells have the potential to be colitogenic in an adaptive transfer model. The development of cTh1 cells was dependent on the co-existence of RORgammat-expressing T cells, suggesting a critical role for the interactions of these cell types in the development of chronic intestinal inflammation.

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Cross-talk between RORgammat+ innate lymphoid cells and intestinal macrophages induces mucosal IL-22 production in Crohn's disease

Mizuno, S., Mikami, Y., Kamada, N., Handa, T., Hayashi, A., Sato, T., Matsuoka, K., Matano, M., Ohta, Y., Sugita, A., Koganei, K., Sahara, R., Takazoe, M., Hisamatsu, T. and Kanai, T.

Inflamm Bowel Dis 20 ( 8 ) 1426 - 34 2014.08

ISSN 1078-0998

BACKGROUND: Interleukin (IL)-22-producing RORgammat innate lymphoid cells (ILCs) play a pivotal role in intestinal immunity. Recent reports demonstrated that ILCs contribute to mucosal protection and intestinal inflammation in mice. In humans, numbers of RORgammat ILCs are significantly increased in the intestine of patients with Crohn's disease (CD), suggesting that ILCs may be associated with intestinal inflammation in CD. However, the mechanism by which ILCs are regulated in the intestine of patients with CD is poorly understood. This study aimed to determine the activation mechanism of intestinal ILCs in patients with CD. METHODS: CD45 lineage marker ILCs were isolated from intestinal lamina propria of patients with CD. ILCs were then subdivided into 4 distinct populations based on the expression of CD56 and CD127. Purified ILC subsets were cocultured with intestinal CD14 macrophages, and IL-22 production was evaluated. RESULTS: CD127CD56 and CD127CD56 ILC, but not CD127CD56 or CD127CD56 ILC, subsets expressed RORgammat and produced IL-22. IL-22 production by these ILC subsets was enhanced when ILCs were cocultured with intestinal macrophages. IL-23 or cell-to-cell contact was required for macrophage-mediated activation of ILCs. IL-22 production by ILCs was perturbed in inflamed mucosa compared with noninflamed mucosa. IL-22 induced the expression of Reg1alpha and Claudin-1 in human intestinal epithelial organoids. CONCLUSIONS: RORgammat ILCs might enhance mucosal barrier function through the upregulation of Reg1alpha through production of IL-22. Although CD14 macrophages augment intestinal inflammation in patients with CD, macrophages also promote a negative feedback pathway through the activation of IL-22 production by RORgammat ILCs.

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Risk and management of intra-abdominal abscess in Crohn's disease treated with infliximab

Yoneno, K., Hisamatsu, T., Matsuoka, K., Okamoto, S., Takayama, T., Ichikawa, R., Sujino, T., Miyoshi, J., Takabayashi, K., Mikami, Y., Mizuno, S., Wada, Y., Yajima, T., Naganuma, M., Inoue, N., Iwao, Y., Ogata, H., Hasegawa, H., Kitagawa, Y., Hibi, T. and Kanai, T.

Digestion 89 ( 3 ) 201 - 8 2014

ISSN 0012-2823

BACKGROUND AND AIMS: Infliximab (IFX) is a monoclonal antibody used to treat patients with Crohn's disease (CD). Intra-abdominal abscess formation is a major complication of CD with negative effects on patient prognosis. We have analyzed risk factors for abscess formation in CD patients treated with IFX. METHODS: CD patients who received IFX between January 2000 and April 2011 at Keio University Hospital were analyzed retrospectively. Risk factors for abscess formation were assessed by univariate and multivariate logistic regression analyses. RESULTS: Intra-abdominal abscess was seen in 15 of 258 patients. Univariate analyses showed serum C-reactive protein (CRP) concentration at 14 weeks after initiation of IFX (p = 0.021), serum albumin concentration at week 0 (p = 0.022) and week 14 (p = 0.004), the presence of anal lesions (p = 0.036), progression of intestine deformation (p = 0.015) and early loss of response to IFX (p < 0.0001) to be risk factors. Multivariate analysis showed that CRP concentration at 14 weeks [odds ratio (OR) 1.361] and loss of IFX response within 6 months (OR 5.361) were independent risk factors. CONCLUSIONS: Abscess formation should be suspected in patients with symptoms of CD recurrence during IFX therapy. Uncontrolled CRP concentration and early loss of response to IFX are risk factors.

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Helper T cell plasticity: impact of extrinsic and intrinsic signals on transcriptomes and epigenomes

Bonelli, M., Shih, H. Y., Hirahara, K., Singelton, K., Laurence, A., Poholek, A., Hand, T., Mikami, Y., Vahedi, G., Kanno, Y. and O'Shea, J. J.

Curr Top Microbiol Immunol 381 279 - 326 2014

ISSN 0070-217X

CD4(+) helper T cells are crucial for autoimmune and infectious diseases; however, the recognition of the many, diverse fates available continues unabated. Precisely what controls specification of helper T cells and preserves phenotypic commitment is currently intensively investigated. In this review, we will discuss the major factors that impact helper T cell fate choice, ranging from cytokines and the microbiome to metabolic control and epigenetic regulation. We will also discuss the technological advances along with the attendant challenges presented by "big data," which allow the understanding of these processes on comprehensive scales.

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Macrophages and dendritic cells emerge in the liver during intestinal inflammation and predispose the liver to inflammation

Mikami, Y., Mizuno, S., Nakamoto, N., Hayashi, A., Sujino, T., Sato, T., Kamada, N., Matsuoka, K., Hisamatsu, T., Ebinuma, H., Hibi, T., Yoshimura, A. and Kanai, T.

PLoS One 9 ( 1 ) e84619 2014

ISSN 1932-6203

The liver is a physiological site of immune tolerance, the breakdown of which induces immunity. Liver antigen-presenting cells may be involved in both immune tolerance and activation. Although inflammatory diseases of the liver are frequently associated with inflammatory bowel diseases, the underlying immunological mechanisms remain to be elucidated. Here we report two murine models of inflammatory bowel disease: RAG-2(-/-) mice adoptively transferred with CD4(+)CD45RB(high) T cells; and IL-10(-/-) mice, accompanied by the infiltration of mononuclear cells in the liver. Notably, CD11b(-)CD11c(low)PDCA-1(+) plasmacytoid dendritic cells (DCs) abundantly residing in the liver of normal wild-type mice disappeared in colitic CD4(+)CD45RB(high) T cell-transferred RAG-2(-/-) mice and IL-10(-/-) mice in parallel with the emergence of macrophages (Mphis) and conventional DCs (cDCs). Furthermore, liver Mphi/cDCs emerging during intestinal inflammation not only promote the proliferation of naive CD4(+) T cells, but also instruct them to differentiate into IFN-gamma-producing Th1 cells in vitro. The emergence of pathological Mphi/cDCs in the liver also occurred in a model of acute dextran sulfate sodium (DSS)-induced colitis under specific pathogen-free conditions, but was canceled in germ-free conditions. Last, the Mphi/cDCs that emerged in acute DSS colitis significantly exacerbated Fas-mediated hepatitis. Collectively, intestinal inflammation skews the composition of antigen-presenting cells in the liver through signaling from commensal bacteria and predisposes the liver to inflammation.

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C-C motif chemokine receptor 9 positive macrophages activate hepatic stellate cells and promote liver fibrosis in mice

Chu, P. S., Nakamoto, N., Ebinuma, H., Usui, S., Saeki, K., Matsumoto, A., Mikami, Y., Sugiyama, K., Tomita, K., Kanai, T., Saito, H. and Hibi, T.

Hepatology 58 ( 1 ) 337 - 50 2013.07

ISSN 0270-9139

UNLABELLED: Chemokine receptors mediate migration of immune cells into the liver, thereby promoting liver inflammation. C-C motif chemokine receptor (CCR) 9(+) macrophages are crucial in the pathogenesis of acute liver inflammation, but the role and underlying mechanisms of this macrophage subset in chronic liver injury and subsequent liver fibrosis are not fully understood. We confirmed that tumor necrosis factor alpha (TNF-alpha)-producing CCR9(+) macrophages accumulated during the initiation of carbon tetrachloride (CCl4 )-induced liver injury, and CCR9 deficiency attenuated the degree of liver damage. Accumulation of CCR9(+) macrophages persisted prominently during the process of liver fibrosis induced by repetitive CCl4 or thioacetamide (TAA)/leptin administration. Increased CCR9 expression was also found on activated hepatic stellate cells (HSCs). Importantly, experimental liver fibrosis was significantly ameliorated in CCR9(-/-) mice compared with wild-type (WT) mice, assessed by alpha-smooth muscle actin (alpha-SMA) immunostain, Sirius red staining, and messenger RNA (mRNA) expression levels of alpha-SMA, collagen 1alpha1, transforming growth factor (TGF)-beta1, and tissue inhibitor of metalloproteinase (TIMP)-1. Accumulated CD11b(+) macrophages in CCl4 -treated WT mice showed marked increases in TNF, NO synthase-2, and TGF-beta1 mRNA expression compared with CCR9(-/-) mice, implying proinflammatory and profibrogenic properties. Hepatic CD11b(+) macrophages from CCl4 -treated WT mice (i.e., CCR9(+) macrophages), but not CD8(+) T lymphocytes or non-CD11b(+) cells, significantly activated HSCs in vitro compared with those from CCR9(-/-) mice. TNF-alpha or TGF-beta1 antagonism attenuated CCR9(+) macrophage-induced HSC activation. Furthermore, C-C motif chemokine ligand (CCL) 25 mediated migration and, to a lesser extent, activation of HSCs in vitro. CONCLUSION: Accumulated CD11b(+) macrophages are critical for activating HSCs through the CCR9/CCL25 axis and therefore promote liver fibrosis. CCR9 antagonism might be a novel therapeutic target for liver fibrosis.

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

Hayashi, A., Sato, T., Kamada, N., Mikami, Y., Matsuoka, K., Hisamatsu, T., Hibi, T., Roers, A., Yagita, H., Ohteki, T., Yoshimura, A. and Kanai, T.

Cell Host Microbe 13 ( 6 ) 711 - 22 2013.06

ISSN 1931-3128

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.

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CCR2 knockout exacerbates cerulein-induced chronic pancreatitis with hyperglycemia via decreased GLP-1 receptor expression and insulin secretion

Nakamura, Y., Kanai, T., Saeki, K., Takabe, M., Irie, J., Miyoshi, J., Mikami, Y., Teratani, T., Suzuki, T., Miyata, N., Hisamatsu, T., Nakamoto, N., Yamagishi, Y., Higuchi, H., Ebinuma, H., Hozawa, S., Saito, H., Itoh, H. and Hibi, T.

Am J Physiol Gastrointest Liver Physiol 304 ( 8 ) G700 - 7 2013.04

ISSN 0193-1857

Glucagon-like peptide-1 (GLP-1) promotes insulin release; however, the relationship between the GLP-1 signal and chronic pancreatitis is not well understood. Here we focus on chemokine (C-C motif) ligand 2 (CCL2) and its receptor (CCR2) axis, which regulates various immune cells, including macrophages, to clarify the mechanism of GLP-1-mediated insulin secretion in chronic pancreatitis in mice. One and multiple series of repetitive cerulein administrations were used to induce acute and chronic cerulein pancreatitis, respectively. Acute cerulein-administered CCR2-knockout (KO) mice showed suppressed infiltration of CD11b(+)Gr-1(low) macrophages and pancreatic inflammation and significantly upregulated insulin secretion compared with paired wild-type (WT) mice. However, chronic cerulein-administered CCR2-KO mice showed significantly increased infiltration of CD11b(+)/Gr-1(-) and CD11b(+)/Gr-1(high) cells, but not CD11b(+)/Gr-1(low) cells, in pancreas with severe inflammation and significantly decreased insulin secretion compared with their WT counterparts. Furthermore, although serum GLP-1 levels in chronic cerulein-administered WT and CCR2-KO mice were comparably upregulated after cerulein administrations, GLP-1 receptor levels in pancreases of chronic cerulein-administered CCR2-KO mice were significantly lower than in paired WT mice. Nevertheless, a significantly higher hyperglycemia level in chronic cerulein-administered CCR2-KO mice was markedly restored by treatment with a GLP-1 analog to a level comparable to the paired WT mice. Collectively, the CCR2/CCL2 axis-mediated CD11b(+)-cell migration to the pancreas is critically involved in chronic pancreatitis-mediated hyperglycemia through the modulation of GLP-1 receptor expression and insulin secretion.

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Immune aspects of the pathogenesis of inflammatory bowel disease

Hisamatsu, T., Kanai, T., Mikami, Y., Yoneno, K., Matsuoka, K. and Hibi, T.

Pharmacol Ther 137 ( 3 ) 283 - 97 2013.03

ISSN 0163-7258

Although the precise etiologies of inflammatory bowel disease (IBD) (ulcerative colitis and Crohn's disease) remain obscure, several reports have indicated that dysfunction of the mucosal immune system plays an important role in its pathogenesis. Recent progress with genome-wide association studies has identified many IBD susceptibility genes. In individuals with genetic risk, abnormal interactions between the host immune system and gut flora, and dysregulation of cellular responses such as autophagy and ER stress, induce an abnormal host immune response in the gut resulting in intestinal inflammation. Research progress animal models in IBD, and in human IBD, has identified several key molecules in IBD pathogenesis such as TNFalpha and adhesion molecules, and molecular targeting therapies based on these molecules have been developed. Here, we review immunological aspects in IBD pathogenesis and the development of immunoregulatory therapy.

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Long-term prognosis of patients with ulcerative colitis treated with cytapheresis therapy

Takayama, T., Kanai, T., Matsuoka, K., Okamoto, S., Sujino, T., Mikami, Y., Hisamatsu, T., Yajima, T., Iwao, Y., Ogata, H. and Hibi, T.

J Crohns Colitis 7 ( 2 ) e49 - 54 2013.03

ISSN 1873-9946

BACKGROUND: Although accumulating studies in Japan show that cytapheresis (CAP) therapy is safe and effective for the induction of remission of moderate or severe ulcerative colitis (UC), the long-term prognosis of UC patients treated with CAP is unknown. The aim of this study was to determine the long-term prognosis of UC patients treated with CAP. METHODS: Ninety patients treated previously with CAP and followed for more than 3 years were evaluated. The rates of operation, readmission, and use or dose-up of corticosteroid were analyzed as long-term prognosis. RESULTS: Following the first course of CAP treatment, 64% of patients showed clinical improvement (> 4-point decrease in the clinical activity index (CAI)), and 49% of patients achieved clinical remission (CAI </= 4). Longer disease duration and lower age at the first CAP treatment correlated significantly with the therapeutic effects of CAP (p = 0.003 and 0.035, respectively). The rates of operation and readmission were significantly lower in patients who showed previous clinical effects of CAP than in those who did not respond to CAP. The rates of operation and readmission were also significantly lower in patients whose treatment was combined with immunomodulators after the initiation of CAP than in patients who did not use immunomodulators. Importantly, the second course of CAP was also effective in most of the patients who showed a clinical response to the first CAP. CONCLUSIONS: Patients who achieve remission after the first CAP therapy may have a good long-term prognosis and a good response to a second CAP therapy even after relapse.

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Dendritic cells administered intrarectally penetrate the intestinal barrier to break intestinal tolerance via Th2-medeiated colitis in mice

Handa, T., Kanai, T., Sato, T., Mikami, Y., Sujino, T., Hayashi, A., Mizuno, S., Matsumoto, A., Hisamatsu, T. and Hibi, T.

Immunol Lett 150 ( 1-2 ) 123 - 9 2013.02

ISSN 0165-2478

Intestinal lamina propria dendritic cells (LPDCs) in mice are known to extend dendrites between the intestinal epithelia and the luminal side when processing luminal antigens. We conducted intrarectal cell transfer experiments of bone marrow-derived dendritic cells (BMDCs) in mice to assess dendritic cell penetration of the intestine. Intrarectally administered GFP(+) BMDCs localized in the colonic LP within 3h and the spleen within 12h after administration. 72h after administration, recipient C57BL/6 mice showed acute diarrhea, and administration of BMDCs (once weekly for 3 weeks) induced intestinal inflammation with increased numbers of recipient macrophages and CD4(+) T cells exhibiting a Th2-mediated immune response. These results demonstrate that DCs actively communicate across the intestinal barrier, and highlight a potential technique for controlling colonic immune tolerance.

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IL-22-producing RORgammat-dependent innate lymphoid cells play a novel protective role in murine acute hepatitis

Matsumoto, A., Kanai, T., Mikami, Y., Chu, P. S., Nakamoto, N., Ebinuma, H., Saito, H., Sato, T., Yagita, H. and Hibi, T.

PLoS One 8 ( 4 ) e62853 2013

ISSN 1932-6203

Retinoid-related orphan receptor (ROR) gammat is known to be related to the development and function of various immunological compartments in the liver, such as Th17 cells, natural killer T (NKT) cells, and innate lymphoid cells (ILCs). We evaluated the roles of RORgammat-expressing cells in mouse acute hepatitis model using RORgammat deficient (RORgammat(-/-)) mice and RAG-2 and RORgammat double deficient (RAG-2(-/-) x RORgammat(-/-)) mice. Acute hepatitis was induced in mice by injection with carbon tetrachloride (CCl4), to investigate the regulation of liver inflammation by RORgammat-expressing cells. We detected RORC expression in three compartments, CD4(+) T cells, NKT cells, and lineage marker-negative SCA-1(+)Thy1(high) ILCs, of the liver of wild type (WT) mice. CCl4-treated RORgammat(-/-) mice developed liver damage in spite of lack of RORgammat-dependent cells, but with reduced infiltration of macrophages compared with WT mice. In this regard, ILCs were significantly decreased in RAG-2(-/-) x RORgammat(-/-) mice that lacked T and NKT cells. Surprisingly, RAG-2(-/-) x RORgammat(-/-) mice developed significantly severer CCl4-induced hepatitis compared with RAG-2(-/-) mice, in accordance with the fact that hepatic ILCs failed to produce IL-22. Lastly, anti-Thy1 monoclonal antibody (mAb), but not anti-NK1.1 mAb or anti-asialo GM1 Ab administration exacerbated liver damage in RAG-2(-/-) mice with the depletion of liver ILCs. Collectively, hepatic RORgammat-dependent ILCs play a part of protective roles in hepatic immune response in mice.

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MyD88-dependent interleukin-10 production from regulatory CD11b(+)Gr-1(high) cells suppresses development of acute cerulein pancreatitis in mice

Koike, Y., Kanai, T., Saeki, K., Nakamura, Y., Nakano, M., Mikami, Y., Yamagishi, Y., Nakamoto, N., Ebinuma, H. and Hibi, T.

Immunol Lett 148 ( 2 ) 172 - 7 2012.12

ISSN 0165-2478

We explored the role of the MyD88 signaling pathway. This pathway mediates the recognition of pathogen-associated molecular patterns and damage-associated molecular patterns via Toll-like receptors (TLRs) and/or IL-1/IL-18 via each cytokine receptor in a murine model of acute pancreatitis induced by cerulein administration. Our analysis revealed that: various TLRs and MyD88 molecules were constitutively expressed in the pancreas of cerulein-treated and untreated wild-type (WT) mice. MyD88(-)/(-) mice administered cerulein developed severe pancreatitis as compared with MyD88(+)/(+) WT mice. The number of IL-10-expressing CD11b(+)Gr-1(high) cells in cerulein-administered MyD88(-)/(-) mice was significantly decreased. This was in accordance with a reciprocal increase in the infiltration of CD4(+) T cells as compared with that in control MyD88(+)/(+) mice. WT mice pretreated with antibiotics and administered cerulein developed milder pancreatitis as compared with control cerulein-administered mice without antibiotic treatment. The MyD88 signaling pathway contributes to the induction of regulatory IL-10-producing macrophages/myeloid-derived suppressor cells, possibly in response to non-bacterial components in the damaged pancreas. These results provide a new concept for therapeutic strategies against acute pancreatitis.

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Anticoagulation therapy dramatically improved severe sigmoiditis with findings resembling inflammatory bowel disease, which was caused by mesenteric venous thrombosis

Mikami, Y., Kanai, T., Iwasaki, E., Naganuma, M., Yamagishi, Y., Shimoda, M., Matsuoka, K., Hisamatsu, T., Iwao, Y., Ogata, H., Nakatsuka, S., Mukai, M. and Hibi, T.

Clin J Gastroenterol 5 ( 6 ) 377 - 82 2012.12

ISSN 1865-7257

Mesenteric venous thrombosis is an insidious disease, with a high mortality rate typically attributed to the long delay in diagnosis. Rapid diagnosis and treatment are important. Here, we present a patient with idiopathic inferior mesenteric venous (IMV) thrombosis. A 65-year-old man presented with constant abdominal pain associated with fever and bloody diarrhea. He was diagnosed with severe ulcerative colitis and was treated with mesalazine and prednisolone. The prednisolone was tapered because of liver dysfunction, and he received total parenteral nutrition for a month. His abdominal pain and bloody diarrhea worsened, and he lost 5 kg of weight. He was then transferred to our institute. Computed tomography showed thickening of the left colon. Colonoscopy showed diffuse colitis with multiple ulcers, large edematous folds, congested mucosa, and stenosis of the sigmoid colon, with sparing of the rectum, raising the possibility of IMV thrombosis. Angiography confirmed IMV thrombosis. Anticoagulation therapy was initiated with intravenous heparin followed by oral warfarin. His abdominal pain and diarrhea resolved, and he was discharged from hospital. Six months later, he remained asymptomatic with normal colonoscopic findings.

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Dysregulated balance of retinoid-related orphan receptor gammat-dependent innate lymphoid cells is involved in the pathogenesis of chronic DSS-induced colitis

Kimura, K., Kanai, T., Hayashi, A., Mikami, Y., Sujino, T., Mizuno, S., Handa, T., Matsuoka, K., Hisamatsu, T., Sato, T. and Hibi, T.

Biochem Biophys Res Commun 427 ( 4 ) 694 - 700 2012.11

ISSN 0006-291X

Retinoid-related orphan receptor (ROR) gammat-expressing and IL-22-producing NKp46(+) innate lymphoid (ILC22) cells reside in the lamina propria of the intestine in mice, suggesting that ILC22 cells contribute to host defense during intestinal damage in models of colitis in mice. Nevertheless, another set of pathological interferon (IFN)-gamma and/or IL-17A-producing innate lymphoid cells (ILC1 and ICL17) may participate in the pathogenesis in different models of colitis. We here showed that RORgammat(+)IL-22(+) ILC22 cells were localized in Thy-1(high)SCA-1(high) and/or Thy-1(high)SCA-1(low) subpopulations of the intestine in normal and dextran sodium sulfate (DSS)-induced colitic RORgammat-sufficient Rag-2(-/-) mice. RORgammat-deficient Rag-2(-/-) mice developed more severe DSS-induced colitis accompanied with lower expression of REG3beta and REG3gamma in the colon, but with a lower ratio and absolute number of IFN-gamma-producing ILC1 cells as compared to control RORgammat-sufficient Rag-2(-/-) mice. Collectively, not only the presence of ILC22 cells but also the balance of protective and pathogenic ILCs may be involved in the prevention of colitis.

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T-helper 17 and interleukin-17-producing lymphoid tissue inducer-like cells make different contributions to colitis in mice

Ono, Y., Kanai, T., Sujino, T., Nemoto, Y., Kanai, Y., Mikami, Y., Hayashi, A., Matsumoto, A., Takaishi, H., Ogata, H., Matsuoka, K., Hisamatsu, T., Watanabe, M. and Hibi, T.

Gastroenterology 143 ( 5 ) 1288 - 1297 2012.11

ISSN 0016-5085

BACKGROUND & AIMS: T helper (Th) 17 cells that express the retinoid-related orphan receptor (ROR) gammat contribute to the development of colitis in mice, yet are found in normal and inflamed intestine. We investigated their development and functions in intestines of mice. METHODS: We analyzed intestinal Th17 cells in healthy and inflamed intestinal tissues of mice. We analyzed expression of lymphotoxin (LT)alpha by Th17 cells and lymphoid tissue inducer-like cells. RESULTS: LTalpha(-/-) and RORgammat(-/-) mice had significantly lower percentages of naturally occurring Th17 cells in the small intestine than wild-type mice. Numbers of CD3(-)CD4(+/-)interleukin-7Ralpha(+)c-kit(+)CCR6(+)NKp46(-) lymphoid tissue inducer-like cells that produce interleukin-17A were increased in LTalpha(-/-) and LTalpha(-/-) x recombination activating gene (RAG)-2(-/-) mice, compared with wild-type mice, but were absent from RORgammat(-/-) mice. Parabiosis of wild-type and LTalpha(-/-) mice and bone marrow transplant experiments revealed that LTalpha-dependent gut-associated lymphoid tissue structures are required for generation of naturally occurring Th17 cells. However, when wild-type or LTalpha(-/-) CD4(+)CD45RB(high) T cells were transferred to RAG-2(-/-) or LTalpha(-/-)xRAG-2(-/-) mice, all groups, irrespective of the presence or absence of LTalpha on the donor or recipient cells, developed colitis and generated Th1, Th17, and Th17/Th1 cells. RAG-2(-/-) mice that received a second round of transplantation, with colitogenic but not naturally occurring Th17 cells, developed intestinal inflammation. The presence of naturally occurring Th17 cells in the colons of mice inhibited development of colitis after transfer of CD4(+)CD45RB(high) T cells and increased the numbers of Foxp3(+) cells derived from CD4(+)CD45RB(high) T cells. CONCLUSIONS: Gut-associated lymphoid tissue structures are required to generate naturally occurring Th17 cells that have regulatory activities in normal intestines of mice, but not for colitogenic Th17 and Th17/Th1 cells during inflammation.

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IgA plasma cells express the negative regulatory co-stimulatory molecule programmed cell death 1 ligand and have a potential tolerogenic role in the intestine

Doi, T., Kanai, T., Mikami, Y., Sujino, T., Jun, L., Ono, Y., Hayashi, A. and Hibi, T.

Biochem Biophys Res Commun 425 ( 4 ) 918 - 23 2012.09

ISSN 0006-291X

To maintain immune homeostasis in the intestine, the intestinal immune system has evolved several tolerogenic mechanisms toward intestinal microflora and food antigens. Although programmed cell death-1 (PD-1) protein has been implicated in immunological tolerance in the intestine and gut-associated lymphoid tissues (GALTs), distribution of its ligands PD-L1 and PD-L2 in the small intestine lamina propria (LP) are unknown. We investigated PD-L1 expression in intestinal LP and found that IgA plasma cells (PCs) were major PD-L1 expressing cells. PD-L1 expression levels on IgA PCs were higher than that on IgG PCs in peripheral lymphoid tissues. IgA PCs expressed antigen-presenting molecule MHC class II and co-stimulatory molecules CD80, CD86, and PD-L2. IgA PCs isolated from intestinal LP exhibited antigen presentation activity, and in the presence of TGF-beta induced FoxP3(+) regulatory T cells, but not IFN-gamma(+) Th1 cells, from naive T cells. Thus, IgA PCs in the intestine may be involved in an immune regulatory role in the intestinal immune system.

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CCR9+ macrophages are required for eradication of peritoneal bacterial infections and prevention of polymicrobial sepsis

Mizukami, T., Kanai, T., Mikami, Y., Hayashi, A., Doi, T., Handa, T., Matsumoto, A., Jun, L., Matsuoka, K., Sato, T., Hisamatsu, T. and Hibi, T.

Immunol Lett 147 ( 1-2 ) 75 - 9 2012.09

ISSN 0165-2478

Sepsis is a systemic inflammatory response to infection associated with multiple organ dysfunction syndrome and a high mortality rate. In septic shock induced by severe peritonitis, early response of peritoneal macrophages against infected microbes is vital in preventing the spread of infection. We found that the mucosal homing receptor CCR9, is induced in peritoneal macrophages in response to inflammatory stimulation. We used a cecal ligation and puncture (CLP) model of sepsis to determine the role of CCR9 with respect to peritoneal macrophages, and controlling peritoneal infection and systemic inflammation. CCR9(-/-) mice showed aggravated septic shock with higher mortality rates compared with wild-type (WT) mice. Six hours after CLP, CCR9(-/-) mice demonstrated a greater inflammatory response. This was associated with higher production of inflammatory cytokines, such as IL-6, TNF and IP-10 in peritoneal lavage compared with WT mice. Although the numbers of peritoneal bacteria were elevated in CCR9(-/-) mice subjected to CLP compared with WT mice, this was normalized in CCR9(-/-) mice subjected to CLP through the adoptive transfer of WT peritoneal macrophages. We conclude that CCR9 is required for recruitment of peritoneal macrophages in the steady state to control systemic sepsis during early phases of peritoneal infection.

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CCR9+ plasmacytoid dendritic cells in the small intestine suppress development of intestinal inflammation in mice

Mizuno, S., Kanai, T., Mikami, Y., Sujino, T., Ono, Y., Hayashi, A., Handa, T., Matsumoto, A., Nakamoto, N., Matsuoka, K., Hisamatsu, T., Takaishi, H. and Hibi, T.

Immunol Lett 146 ( 1-2 ) 64 - 9 2012.08

ISSN 0165-2478

Almost all mice lacking specific molecules associated with regulatory T cells or barrier function develop intestinal inflammation in the colon, but not in the small intestine (SI). Therefore, intestinal homeostasis of the SI may be tightly controlled by other mechanisms. To determine the role of CCR9(+) plasmacytoid dendritic cells (pDCs) in intestinal homeostasis of the SI we transferred CD4(+)CD45RB(high) T cells into ccr9(-/-)xrag-2(-/-) mice. We showed that CCL25, a counterpart chemokine for CCR9, is constitutively expressed in the SI but not the colon and spleen of rag-2(-/-) or ccr9(-/-)xrag-2(-/-) mice before or after transfer of CD4(+)CD45RB(high) T cells. The ccr9(-/-)xrag-2(-/-) mice did not develop spontaneous intestinal inflammation in the SI and colon. Mice of both genotype where CD4(+)CD45RB(high) T cells were transferred developed colitis. However, the ccr9(-/-)xrag-2(-/-) mice also developed ileitis with marked infiltration of Th1 cells. These results suggest that CCR9(+) pDCs are possibly small, regulatory, antigen-presenting cells of the intestine that suppress intestinal inflammation.

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RORgammat-dependent IL-17A-producing cells in the pathogenesis of intestinal inflammation

Kanai, T., Mikami, Y., Sujino, T., Hisamatsu, T. and Hibi, T.

Mucosal Immunol 5 ( 3 ) 240 - 7 2012.05

ISSN 1933-0219

The hypothesis of helper T (T(h))1/T(h)2 cytokine balance proposed by Mosmann and Coffman is often invoked to explain the development of inflammatory diseases, including inflammatory bowel diseases (IBD). Recently, however, a newly identified class of T(h) cells-T(h)17 cells, which produce T(h)17 family cytokines-has been recognized as an essential subpopulation in the development of almost all kinds of human and animal inflammatory diseases, rather than T(h)1 and T(h)2 cells. A representative T(h)17 family cytokine, interleukin (IL)-17A, is produced by not only T(h)17 cells, but also by other types of cells, such as T-cell receptor gammadelta T cells, natural killer (NK) T cells, NK cells, myeloid cells, and innate lymphoid cells, which may also be critically involved in the initiation and persistence of IBD. Here we review recent advances in the study of such IL-17A-producing cells in the pathogenesis of IBD.

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