Details of a Researcher - Mikami, Yohei

Papers - Mikami, Yohei

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Plasmacytoid dendrtic cells protect against acute liver injury via IL-35

Koda Yuzo, Nakamoto Nobuhiro, Chu Po-Sung, Yoshida Aya, Mikami Yohei, Teratani Toshiaki, Kanai Takanori

JOURNAL OF HEPATOLOGY 73 S565 - S566 2020.08

ISSN 0168-8278

Clinical and endoscopic characteristics of pyogenic granuloma in the small intestine: A case series with literature review

Hayashi Y., Dr N.H., Takabayashi K., Limpias Kamiya K.J.L., Mutaguchi M., Miyanaga R., Hirata K., Fukuhara S., Mikami Y., Sujino T., Masugi Y., Naganuma M., Ogata H., Kanai T.

Internal Medicine (Internal Medicine) 59 ( 4 ) 501 - 505 2020.02

ISSN 09182918

© 2020 Japanese Society of Internal Medicine. All rights reserved. Pyogenic granuloma (PG) generally appears in the skin or oral cavity, but rarely occurs in the small intestine, where it can cause bleeding. To date, only 35 cases of small intestinal PG have been reported in the English literature. We retrospectively collected information from the clinical records of seven cases of small intestinal PG that were managed in our hospital and summarized the characteristics. Further information on the clinical characteristics was obtained from the literature. Capsule endoscopy, useful for identifying the source of hemorrhage in obscure gastrointestinal bleeding, can detect PGs. Treatment can often be accomplished with endoscopic mucosal resection.

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5-Aminosalicylic acid intolerance is associated with a risk of adverse clinical outcomes and dysbiosis in patients with ulcerative colitis

Mizuno S., Ono K., Mikami Y., Naganuma M., Fukuda T., Minami K., Masaoka T., Terada S., Yoshida T., Saigusa K., Hirahara N., Miyata H., Suda W., Hattori M., Kanai T.

Intestinal Research (Intestinal Research) 18 ( 1 ) 69 - 78 2020.01

ISSN 15989100

© 2020. Korean Association for the Study of Intestinal Diseases. Background/Aims: 5-Aminosalicylic acid (ASA) causes intolerance reactions in some patients. This study was performed to examine the prognosis of patients with ulcerative colitis (UC) and 5-ASA intolerance, and to evaluate the potential interaction between 5-ASA intolerance and the intestinal microbiota. Methods: We performed a retrospective cohort study of patients with UC who visited participating hospitals. The primary endpoint was to compare the incidence of hospitalization within 12 months between the 5-ASA intolerance group and the 5-ASA tolerance group. The secondary endpoint was to compare the risk of adverse clinical outcomes after the start of biologics between the 2 groups. We also assessed the correlation between 5-ASA intolerance and microbial change in an independently recruited cohort of patients with UC. Results: Of 793 patients, 59 (7.4%) were assigned to the 5-ASA intolerance group and 734 (92.5%) were assigned to the 5-ASA tolerance group. The admission rate and incidence of corticosteroid use were significantly higher in the intolerance than tolerance group (P<0.001). In 108 patients undergoing treatment with anti-tumor necrosis factor biologics, 5-ASA intolerance increased the incidence of additional induction therapy after starting biologics (P<0.001). The 5-ASA intolerance group had a greater abundance of bacteria in the genera Faecalibacterium, Streptococcus, and Clostridium than the 5-ASA tolerance group (P<0.05). Conclusions: In patients with UC, 5-ASA intolerance is associated with a risk of adverse clinical outcomes and dysbiosis. Bacterial therapeutic optimization of 5-ASA administration may be important for improving the prognosis of patients with UC.

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Complete endoscopic remission is not only associated with higher mucosal concentrations of 5-aminosalicylic acid but also with N-acetyl-5-aminosalicylic acid in patients with ulcerative colitis

Fukuda T., Naganuma M., Takabayashi K., Hagihara Y., Tanemoto S., Nomura E., Yoshimatsu Y., Sugimoto S., Nanki K., Mizuno S., Mikami Y., Fukuhara K., Suzino T., Mutaguchi M., Inoue N., Ogata H., Iwao Y., Kanai T.

JOURNAL OF CROHNS & COLITIS 14 S522 - S523 2020.01

ISSN 1873-9946

The liver–brain–gut neural arc maintains the T<inf>reg</inf> cell niche in the gut

Teratani T., Mikami Y., Nakamoto N., Suzuki T., Harada Y., Okabayashi K., Hagihara Y., Taniki N., Kohno K., Sibata S., Miyamoto K., Ishigame H., Chu P.S., Sujino T., Suda W., Hattori M., Matsui M., Okada T., Okano H., Inoue M., Yada T., Kitagawa Y., Yoshimura A., Tanida M., Tsuda M., Iwasaki Y., Kanai T.

Nature (Nature) 585 ( 7826 ) 591 - 596 2020

ISSN 00280836

© 2020, The Author(s), under exclusive licence to Springer Nature Limited. The gut–brain axis, a reciprocal interaction between the central nervous system (CNS) and peripheral intestinal functions, is conceptually feasible from recent clinical and experimental evidence showing mutual interactions between the CNS and gut microbiota that are closely associated with the bidirectional effects of inflammatory bowel diseases (IBDs) and CNS disorders1–4. Despite recent advances in our understanding of neuroimmune interactions, it remains unclear how the gut and brain communicate to maintain gut immune homeostasis, including induction and maintenance of peripheral regulatory T cells (pTreg cells) and what environmental cues prompt the host to protect host from development of IBDs. Here, we report a novel liver-brain-gut neural arc that ensures proper differentiation and maintenance of pTreg cells in the gut. The hepatic vagal sensory afferents were responsible for indirectly sensing the gut microenvironment and relaying the sensory inputs to the nucleus tractus solitarius of the brainstem, and ultimately to the vagal parasympathetic nerves and enteric neurons. Surgical and chemical perturbation of the vagal sensory afferents at the hepatic afferent level significantly impaired colonic pTreg cells, which was attributed to impairment of aldehyde dehydrogenase (ALDH) expression and retinoic acid (RA) synthesis by intestinal antigen-presenting cells (APCs). Muscarinic Ach receptor (mAChR) activation directly induced ALDH gene expression both in human and mouse colonic APCs, whereas genetic ablation of mAChRs abolished APC excitement in vitro. Disruption of left vagal sensory afferents from the liver to the brainstem in colitis models reduced the colonic pTreg pool, resulting in increased susceptibility to colitis. These results demonstrate that the novel vago-vagal liver–brain–gut reflex arc tunes the number of pTreg cells and maintains the gut homeostasis. Intervening in this autonomic feedback feed-forward system could help develop new therapeutic strategies to treat or prevent immunological disorders of the gut.

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Mucosal concentrations of N-acetyl-5-aminosalicylic acid related to endoscopic activity in ulcerative colitis patients with mesalamine

Fukuda T., Naganuma M., Takabayashi K., Hagihara Y., Tanemoto S., Nomura E., Yoshimatsu Y., Sugimoto S., Nanki K., Mizuno S., Mikami Y., Fukuhara K., Sujino T., Mutaguchi M., Inoue N., Ogata H., Iwao Y., Abe T., Kanai T.

Journal of Gastroenterology and Hepatology (Australia) (Journal of Gastroenterology and Hepatology (Australia)) 35 ( 11 ) 1878 - 1885 2020

ISSN 08159319

© 2020 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd Background and Aim: 5-Aminosalicylic acid (5-ASA) is a fundamental treatment for mild-to-moderate ulcerative colitis (UC). 5-ASA is taken up into the colonic mucosa and metabolized to N-acetyl-5-ASA (Ac-5-ASA). Few studies have assessed whether mucosal 5-ASA and Ac-5-ASA concentrations are associated with endoscopic remission. This study aimed to investigate differences in 5-ASA and Ac-5-ASA concentrations according to endoscopic activity. Methods: This single-center, prospective, cross-sectional study was conducted between March 2018 and February 2019. UC patients who were administered with 5-ASA medication for at least 8 weeks before sigmoidoscopy were enrolled. Mucosal 5-ASA and Ac-5-ASA concentrations were measured using liquid chromatography with tandem mass spectrometry. The primary endpoint was defined as the difference in mucosal concentrations of 5-ASA and Ac-5-ASA, according to the Mayo endoscopic subscore (MES). Results: Mucosal concentrations were analyzed in 50 patients. In the sigmoid colon, the median 5-ASA concentration in patients with MES of 0 (17.3 ng/mg) was significantly higher than MES ≥ 1 (6.4 ng/mg) (P = 0.019). The median 5-ASA concentrations in patients with Ulcerative Colitis Endoscopic Index of Severity ≤ 1 (16.4 ng/mg) were also significantly higher than in patients with Ulcerative Colitis Endoscopic Index of Severity ≥ 2 (4.63 ng/mg) (P = 0.047). In the sigmoid colon, the concentration of Ac-5-ASA was higher in patients with MES of 0 (21.2 ng/mg) than in patients with MES ≥ 1 (5.81 ng/mg) (P = 0.022). Conclusions: The present study showed that mucosal Ac-5-ASA concentrations, as well as 5-ASA concentrations, are higher in UC patients with endoscopic remission. Ac-5-ASA may be useful for a biomarker of 5-ASA efficacy.

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Significance of endoscopic deep small bowel evaluation using balloon-assisted enteroscopy for Crohn’s disease in clinical remission

Takabayashi K., Hosoe N., Kato M., Hayashi Y., Nanki K., Fukuhara K., Mikami Y., Mizuno S., Sujino T., Mutaguchi M., Naganuma M., Yahagi N., Ogata H., Kanai T.

Journal of Gastroenterology (Journal of Gastroenterology) 56 ( 1 ) 25 - 33 2020

ISSN 09441174

© 2020, Japanese Society of Gastroenterology. Background: Small bowel lesions of Crohn’s disease (CD) are known to be associated with a poor prognosis; however, endoscopic healing leads to favorable patients’ outcome. The aim of this study was to clarify the clinical impact of assessing deep small bowel lesions (DSB) using balloon-assisted enteroscopy (BAE) on CD patients in clinical remission. Methods: From January 2012 to July 2018, a total of 100 CD patients in clinical remission were enrolled to undergo trans-anal enteroscopy using single-balloon enteroscope. Endoscopic evaluations at the terminal ileum (TI) were performed using a partial Simple Endoscopic Score for CD (pSES-CD). Endoscopic evaluations at the DSB used a modified partial SES-CD (mpSES-CD). We evaluated the factors associated with relapse, and the correlation of endoscopic score between the TI and DSB. For this study, relapse was defined as hospitalization within a year from enteroscopy. Results: 30 patients (30.0%) relapsed within a year from enteroscopy. Multivariate logistic regression analysis revealed that the Harvey–Bradshaw Index (OR 1.77, 95% CI 1.18–2.65; p = 0.003) and an mpSES-CD at DSB (OR 3.10, 95% CI 1.86–5.15; p = 0.001) were independent predictors for relapse, whereas a SES-CD at the TI did not exhibit independence. There was a significant correlation trend between the relapse rate and greater than 5 points of an mpSES-CD at DSB; however, there was no correlation between the relapse rate and pSES-CD at the TI. Conclusion: Even when Crohn's disease is in remission, it is important to evaluate DSB using BAE to assess endoscopic mucosal healing.

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Neuropeptide CGRP Limits Group 2 Innate Lymphoid Cell Responses and Constrains Type 2 Inflammation

Nagashima H., Mahlakõiv T., Shih H., Davis F., Meylan F., Huang Y., Harrison O., Yao C., Mikami Y., Urban J., Caron K., Belkaid Y., Kanno Y., Artis D., O'Shea J.

Immunity (Immunity) 51 ( 4 ) 682 - 695.e6 2019.10

ISSN 10747613

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Plasmacytoid dendritic cells protect against immune-mediated acute liver injury via IL-35

Koda Y., Nakamoto N., Chu P., Ugamura A., Mikami Y., Teratani T., Tsujikawa H., Shiba S., Taniki N., Sujino T., Miyamoto K., Suzuki T., Yamaguchi A., Morikawa R., Sato K., Sakamoto M., Yoshimoto T., Kanai T.

Journal of Clinical Investigation (Journal of Clinical Investigation) 129 ( 8 ) 3201 - 3213 2019.08

ISSN 00219738

© 2019, American Society for Clinical Investigation. Acute liver failure (ALF) is a life-threatening condition, and liver transplantation is the only therapeutic option. Although immune dysregulation is central to its pathogenesis, the precise mechanism remains unclear. Here, we show that the number of peripheral and hepatic plasmacytoid DCs (pDCs) decrease during acute liver injury in both humans and mice. Selective depletion of pDCs in Siglechdtr/+ mice exacerbated concanavalin A–induced acute liver injury. In contrast, adoptively transferred BM-derived pDCs preferentially accumulated in the inflamed liver and protected against liver injury. This protective effect was independent of TLR7 and TLR9 signaling, since a similar effect occurred following transfer of MyD88-deficient pDCs. Alternatively, we found an unexpected immunosuppressive role of pDCs in an IL-35–dependent manner. Both Il12a and Ebi3, heterodimeric components of IL-35, were highly expressed in transferred pDCs and CD4+CD25+ Tregs. However, the protective effect of pDC transfer was completely lost in mice depleted of Tregs by anti-CD25 antibody. Moreover, pDCs derived from IL-35–deficient mice had less of a protective effect both in vivo and in vitro even in the presence of Tregs. These results highlight a unique aspect of pDCs in association with Tregs, serving as a guide for immunotherapeutic options in ALF.

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CLINICAL UTILITY OF BALLOON ASSISTED ENTEROSCOPY TO EVALUATE DEEP SMALL BOWEL LESIONS OF CROHN'S DISEASE

Takabayashi Kaoru, Hosoe Naoki, Kato Motohiko, Hayashi Yukie, Miyanaga Ryoichi, Sugimoto Shinya, Nanki Kosaku, Kimura Kayoko, Mikami Yohei, Mizuno Shinta, Mutaguchi Makoto, Sujino Tomohisa, Naganuma Makoto, Ogata Haruhiko, Kanai Takanori

GASTROINTESTINAL ENDOSCOPY 89 ( 6 ) AB363 - AB363 2019.06

ISSN 0016-5107

Retinoic Acid Receptor Alpha Represses a Th9 Transcriptional and Epigenomic Program to Reduce Allergic Pathology

Schwartz D., Farley T., Richoz N., Yao C., Shih H., Petermann F., Zhang Y., Sun H., Hayes E., Mikami Y., Jiang K., Davis F., Kanno Y., Milner J., Siegel R., Laurence A., Meylan F., O'Shea J.

Immunity (Immunity) 50 ( 1 ) 106 - 120.e10 2019.01

ISSN 10747613

© 2018 CD4+ T helper (Th) differentiation is regulated by diverse inputs, including the vitamin A metabolite retinoic acid (RA). RA acts through its receptor RARα to repress transcription of inflammatory cytokines, but is also essential for Th-mediated immunity, indicating complex effects of RA on Th specification and the outcome of the immune response. We examined the impact of RA on the genome-wide transcriptional response during Th differentiation to multiple subsets. RA effects were subset-selective and were most significant in Th9 cells. RA globally antagonized Th9-promoting transcription factors and inhibited Th9 differentiation. RA directly targeted the extended Il9 locus and broadly modified the Th9 epigenome through RARα. RA-RARα activity limited murine Th9-associated pulmonary inflammation, and human allergic inflammation was associated with reduced expression of RA target genes. Thus, repression of the Th9 program is a major function of RA-RARα signaling in Th differentiation, arguing for a role for RA in interleukin 9 (IL-9) related diseases.

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Toll-Like Receptor 7 Agonist–Induced Dermatitis Causes Severe Dextran Sulfate Sodium Colitis by Altering the Gut Microbiome and Immune Cells

Kiyohara H., Sujino T., Teratani T., Miyamoto K., Arai M., Nomura E., Harada Y., Aoki R., Koda Y., Mikami Y., Mizuno S., Naganuma M., Hisamatsu T., Kanai T.

Cellular and Molecular Gastroenterology and Hepatology (Cellular and Molecular Gastroenterology and Hepatology) 7 ( 1 ) 135 - 156 2019

ISSN 2352-345X

© 2018 The Authors Background & Aims: Psoriasis and inflammatory bowel disease (IBD) are both chronic inflammatory diseases occurring in the skin and gut, respectively. It is well established that psoriasis and IBD have high concordance rates, and similar changes in immune cells and microbiome composition have been reported in both conditions. To study this connection, we used a combination murine model of psoriatic dermatitis and colitis in which mice were treated topically with the Toll-like receptor 7 agonist imiquimod (IMQ) and fed dextran sulfate sodium (DSS). Methods: We applied IMQ topically to B6 mice (IMQ mice) and subsequently fed them 2% DSS in their drinking water. Disease activity and immune cell phenotypes were analyzed, and the microbial composition of fecal samples was investigated using 16S ribosomal RNA sequencing. We transplanted feces from IMQ mice to germ-free IQI/Jic (IQI) mice and fed them DSS to assess the effect of the gut microbiome on disease. Results: We first confirmed that IMQ mice showed accelerated DSS colitis. IMQ mice had decreased numbers of IgD + and IgM + B cells and increased numbers of non–cytokine-producing macrophages in the gut. Moreover, the gut microbiomes of IMQ mice were perturbed, with significant reductions of Lactobacillus johnsonii and Lactobacillus reuteri populations. Germ-free mice transplanted with feces from IMQ mice, but not with feces from untreated mice, also developed exacerbated DSS colitis. Conclusions: These results suggest that skin inflammation may contribute to pathogenic conditions in the gut via immunologic and microbiological changes. Our finding of a novel potential skin–gut interaction provides new insights into the coincidence of psoriasis and IBD.

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Epigenetic regulation of T helper cells and intestinal pathogenicity

Hagihara Y., Yoshimatsu Y., Mikami Y., Takada Y., Mizuno S., Kanai T.

Seminars in Immunopathology (Seminars in Immunopathology) 41 ( 3 ) 379 - 399 2019

ISSN 18632297

© 2019, Springer-Verlag GmbH Germany, part of Springer Nature. Inflammatory bowel diseases (IBDs) are characterized by relapsing and remitting chronic intestinal inflammation. Previous studies have demonstrated the contributions of genetic background, environmental factors (food, microbiota, use of antibiotics), and host immunity in the development of IBDs. More than 200 genes have been shown to influence IBD susceptibility, most of which are involved in immunity. The vertebrate immune system comprises a complex network of innate and adaptive immune cells that protect the host from infection and cancer. Dysregulation of the mutualistic relationship between the immune system and the gut environment results in IBD. Considering the fundamental role of epigenetic regulation in immune cells, epigenetic mechanisms, particularly in T helper (Th) cells, may play a major role in the complex regulation of mucosal immunity. Epigenetic regulation and dysregulation of Th cells are involved in the maintenance of intestinal homeostasis and its breakdown in IBD.

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Development of an Indigo Naturalis Suppository for Topical Induction Therapy in Patients with Ulcerative Colitis

Yoshimatsu Y., Naganuma M., Sugimoto S., Tanemoto S., Umeda S., Fukuda T., Nomura E., Yoshida K., Ono K., Mutaguchi M., Nanki K., Mizuno S., Mikami Y., Fukuhara K., Sujino T., Takabayashi K., Ogata H., Iwao Y., Kanai T.

Digestion (Digestion) 101 ( 4 ) 492 - 498 2019

ISSN 00122823

© 2019 S. Karger AG, Basel. All rights reserved. Background: Indigo naturalis (IN) consists of ligands for the aryl hydrocarbon receptor and exhibits anti-inflammatory effects. Previously, we demonstrated that an 8-week treatment with oral IN is effective in inducing a clinical response in patients with ulcerative colitis (UC). Some UC patients with proctitis are refractory to topical mesalamine or corticosteroids and therefore require an alternative topical treatment. Objectives: We aimed to prospectively evaluate the safety and efficacy of IN suppositories in UC patients. Method: We performed an open-label, single-center, prospective pilot study from February 2018 to October 2018. A total of 10 patients with active UC, who had moderate to severe inflammation from the rectum to the sigmoid colon, were enrolled. The patients received a daily dose of 50 mg IN suppository for 4 weeks. The primary endpoint was safety at week 4. Results: Although 1 patient experienced anal pain, no serious adverse events were observed. At week 4, the rates of clinical remission and mucosal healing were 30 and 40%, respectively. Mayo rectal bleeding subscores significantly improved after treatment (1.80 ± 0.13 vs. 0.90 ± 0.28; p = 0.009). Approximately 80% of the patients with a baseline Mayo endoscopic subscore in the rectum (r-MES) of 2 achieved mucosal healing, but those with a baseline r-MES of 3 did not. Conclusions: We found that 4 weeks of IN suppository can be tolerated by UC patients, but its efficacy was limited by the severity of the disease. Further investigation will be needed in order to confirm the optimum dose of IN suppository for patients with UC.

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Human Intestinal Organoids Maintain Self-Renewal Capacity and Cellular Diversity in Niche-Inspired Culture Condition

Fujii M., Matano M., Toshimitsu K., Takano A., Mikami Y., Nishikori S., Sugimoto S., Sato T.

Cell Stem Cell (Cell Stem Cell) 23 ( 6 ) 787 - 793.e6 2018.12

ISSN 19345909

© 2018 Elsevier Inc. Cellular diversity that shapes tissue architecture and function is governed by multiple niche signals. Nonetheless, maintaining cellular diversity in human intestinal organoids has been challenging. Based on niche ligands present in the natural stem cell milieu, we establish a refined organoid culture condition for intestinal epithelia that allows human intestinal organoids to concurrently undergo multi-differentiation and self-renewal. High-throughput screening reveals that the combination of insulin-like growth factor 1 (IGF-1) and fibroblast growth factor 2 (FGF-2) enhances the clonogenic capacity and CRISPR-genome engineering efficiency of human intestinal stem cells. The combination equally enables long-term culture of a range of intestinal organoids, including rat small intestinal organoids. Droplet-based single-cell RNA sequencing further illustrates the conservation of the native cellular diversity in human small intestinal organoids cultured with the refined condition. The modified culture protocol outperforms the conventional method and offers a viable strategy for modeling human intestinal tissues and diseases in an in vivo relevant context. Sato and colleagues develop a modified culture condition for human intestinal organoids that improves the culture efficiency and maintains their long-term multi-differentiation capacity. scRNA-seq of human small intestinal crypts and organoids demonstrates that in vivo cellular diversity can be preserved in organoids cultured with the refined condition.

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Non-classical monocytes as mediators of tissue destruction in arthritis

Puchner, A., Saferding, V., Bonelli, M., Mikami, Y., Hofmann, M., Brunner, J. S., Caldera, M., Goncalves-Alves, E., Binder, N. B., Fischer, A., Simader, E., Steiner, C. W., Leiss, H., Hayer, S., Niederreiter, B., Karonitsch, T., Koenders, M. I., Podesser, B. K., O'Shea, J. J., Menche, J., Smolen, J. S., Redlich, K. and Bluml, S.

Ann Rheum Dis (Annals of the rheumatic diseases) 77 ( 10 ) 1490 - 1497 2018.10

ISSN 0003-4967

OBJECTIVES: Bone destruction in rheumatoid arthritis is mediated by osteoclasts (OC), which are derived from precursor cells of the myeloid lineage. The role of the two monocyte subsets, classical monocytes (expressing CD115, Ly6C and CCR2) and non-classical monocytes (which are CD115 positive, but low in Ly6C and CCR2), in serving as precursors for OC in arthritis is still elusive. METHODS: We investigated CCR2(-/-) mice, which lack circulating classical monocytes, crossed into hTNFtg mice for the extent of joint damage. We analysed monocyte subsets in hTNFtg and K/BxN serum transfer arthritis by flow cytometry. We sorted monocyte subsets and analysed their potential to differentiate into OC and their transcriptional response in response to RANKL by RNA sequencing. With these data, we performed a gene ontology enrichment analysis and gene set enrichment analysis. RESULTS: We show that in hTNFtg arthritis local bone erosion and OC generation are even enhanced in the absence of CCR2. We further show the numbers of non-classical monocytes in blood are elevated and are significantly correlated with histological signs of joint destruction. Sorted non-classical monocytes display an increased capacity to differentiate into OCs. This is associated with an increased expression of signal transduction components of RANK, most importantly TRAF6, leading to an increased responsiveness to RANKL. CONCLUSION: Therefore, non-classical monocytes are pivotal cells in arthritis tissue damage and a possible target for therapeutically intervention for the prevention of inflammatory joint damage.

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Innate lymphoid cells in organ fibrosis

Mikami, Y., Takada, Y., Hagihara, Y. and Kanai, T.

Cytokine Growth Factor Rev 42 27 - 36 2018.08

ISSN 1359-6101

Innate lymphoid cells (ILCs) are a recently identified family of lymphoid effector cells. ILCs are mainly clustered into 3 groups based on their unique cytokine profiles and transcription factors typically attributed to the subsets of T helper cells. ILCs have a critical role in the mucosal immune response through promptly responding to pathogens and producing large amount of effector cytokines of type 1, 2, or 3 responses. In addition to the role of early immune responses against infections, ILCs, particularly group 2 ILCs (ILC2), have recently gained attention for modulating remodeling and fibrosis especially in the mucosal tissues. Herein, we overview the current knowledge in this area, highlighting roles of ILCs on fibrosis in the mucosal tissues, especially focusing on the gut and lung. We also discuss some new directions for future research by extrapolating from knowledge derived from studies on Th cells.

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NCR(+) ILC3 maintain larger STAT4 reservoir via T-BET to regulate type 1 features upon IL-23 stimulation in mice

Mikami, Y., Scarno, G., Zitti, B., Shih, H. Y., Kanno, Y., Santoni, A., O'Shea, J. J. and Sciume, G.

Eur J Immunol (European Journal of Immunology) 48 ( 7 ) 1174 - 1180 2018.07

ISSN 0014-2980

Innate lymphoid cells (ILCs) producing IL-22 and/or IL-17, designated as ILC3, comprise a heterogeneous subset of cells involved in regulation of gut barrier homeostasis and inflammation. Exogenous environmental cues in conjunction with regulated expression of endogenous factors are key determinants of plasticity of ILC3 toward the type 1 fate. Herein, by using mouse models and transcriptomic approaches, we defined at the molecular level, initial events driving ILC3 expressing natural cytotoxicity receptors (NCR(+) ILC3) to acquire type 1 features. We observed that NCR(+) ILC3 exhibited high basal expression of the signal-dependent transcription factor STAT4 due to T-BET, leading to predisposed potential for the type 1 response. We found that the prototypical inducer of type 3 response, IL-23, played a predominant role over IL-12 by accessing STAT4 and preferentially inducing its phosphorylation in ILC3 expressing T-BET. The early effector program driven by IL-23 was characterized by the expression of IL-22, followed by a production of IFN-gamma, which relies on STAT4, T-BET and required chromatin remodeling of the Ifng locus. Altogether, our findings shed light on a feed-forward mechanism involving STAT4 and T-BET that modulates the outcome of IL-23 signaling in ILC3.

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Intestinal barrier regulates immune responses in the liver via IL-10-producing macrophages

Taniki, N., Nakamoto, N., Chu, P. S., Mikami, Y., Amiya, T., Teratani, T., Suzuki, T., Tsukimi, T., Fukuda, S., Yamaguchi, A., Shiba, S., Miyake, R., Katayama, T., Ebinuma, H. and Kanai, T.

JCI Insight (JCI insight) 3 ( 12 ) 2018.06

ISSN 2379-3708

The gut-liver axis is of clinical importance as a potential therapeutic target in a wide range of liver diseases; however, the mechanisms underlying interactions between microbial products and immune responses in the liver remain unknown. In this study, we demonstrated that IL-10-producing macrophages contribute to immune tolerance in the inflamed liver under intestinal barrier disruption in a murine tandem model of dextran sulfate sodium (DSS) colitis and concanavalin A (Con A) hepatitis. Intestinal barrier disruption protected mice from subsequent liver injury, and the severity of colitis directly affected susceptibility to such injury. The protective effect of DSS-Con A was canceled in gut-sterilized mice, suggesting that gut microbiota play a substantial role in this process. Altered gut microbiota and their metabolites, along with a disrupted intestinal barrier, directly gave rise to immunological permissiveness in the inflamed liver. We identified 1-methylnicotinamide (1-MNA) as a candidate metabolite capable of suppressing liver injury with the potential to induce IL-10-producing macrophages. Consistently, expression of nicotinamide N-methyltransferase, which converts nicotinamide to 1-MNA, was upregulated in the liver of DSS-Con A mice, and this effect was abrogated by gut sterilization. Collectively, our results provide a mechanistic insight into the regulation of immunological balance in the liver via the gut-liver axis.

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Cholesterol 25-hydroxylase expressing CD4(+) T cell regulates skin inflammation

Takahashi H., Nomura H., Iriki H., Kubo A., Mukai M., Sasaki T., Mikami Y., O'Shea J., Amagai M.

JOURNAL OF INVESTIGATIVE DERMATOLOGY 138 ( 5 ) S3 - S3 2018.05

ISSN 0022-202X

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