Details of a Researcher - Mikami, Yohei

Papers - Mikami, Yohei

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Myeloid TLR4 signaling promotes post-injury withdrawal resolution of murine liver fibrosis

Takimoto Y., Chu P.s., Nakamoto N., Hagihara Y., Mikami Y., Miyamoto K., Morikawa R., Teratani T., Taniki N., Fujimori S., Suzuki T., Koda Y., Ishihara R., Ichikawa M., Honda A., Kanai T.

iScience (iScience) 26 ( 3 ) 106220 2023.03

The fate of resolution of liver fibrosis after withdrawal of liver injury is still incompletely elucidated. Toll-like receptor 4 (TLR4) in tissue fibroblasts is pro-fibrogenic. After withdrawal of liver injury, we unexpectedly observed a significant delay of fibrosis resolution as TLR4 signaling was pharmacologically inhibited in vivo in two murine models. Single-cell transcriptome analysis of hepatic CD11b+ cells, main producers of matrix metalloproteinases (MMPs), revealed a prominent cluster of restorative Tlr4-expressing Ly6c2-low myeloid cells. Delayed resolution after gut sterilization suggested its microbiome-dependent nature. Enrichment of a metabolic pathway linking to a significant increase of bile salt hydrolase-possessing family Erysipelotrichaceae during resolution. Farnesoid X receptor-stimulating secondary bile acids including 7-oxo-lithocholic acids upregulated MMP12 and TLR4 in myeloid cells in vitro. Fecal material transplant in germ-free mice confirmed phenotypical correlations in vivo. These findings highlight a pro-fibrolytic role of myeloid TLR4 signaling after injury withdrawal and may provide targets for anti-fibrotic therapy.

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Network Approaches to Uncover Pathogenesis and Therapeutic Targets of Inflammatory Bowel Diseases.

Mikami Y, Kanai T

The Keio journal of medicine (Keio Journal of Medicine) 72 ( 2 ) 29 - 43 2023.03

ISSN 0022-9717

Inflammatory bowel diseases (IBD) are currently recognized to involve chronic intestinal inflammation in genetically susceptible individuals. Patients with IBD mainly develop gastrointestinal inflammation, but it is sometimes accompanied by extraintestinal manifestations such as arthritis, erythema nodo-sum, episcleritis, pyoderma gangrenosum, uveitis, and primary sclerosing cholangitis. These clinical aspects imply the importance of interorgan networks in IBD. In the gastrointestinal tract, immune cells are influenced by multiple local environmental factors including microbiota, dietary environment, and intercellular networks, which further alter molecular networks in immune cells. Therefore, decipher-ing networks at interorgan, intercellular, and intracellular levels should help to obtain a comprehensive understanding of IBD. This review focuses on the intestinal immune system, which governs the physiological and pathological functions of the digestive system in harmony with the other organs. (DOI: 10.2302/kjm.2022-0015-IR; Keio J Med 72 (2): 29–43, June 2023).

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Diagnosis and Clinical Features of Perianal Lesions in Newly Diagnosed Crohn's Disease: Subgroup Analysis from Inception Cohort Registry Study of Patients with Crohn's Disease (iCREST-CD).

Yamamoto T, Nakase H, Watanabe K, Shinzaki S, Takatsu N, Fujii T, Okamoto R, Matsuoka K, Yamada A, Kunisaki R, Matsuura M, Shiga H, Bamba S, Mikami Y, Shimoyama T, Motoya S, Torisu T, Kobayashi T, Ohmiya N, Saruta M, Matsuda K, Matsumoto T, Maemoto A, Murata Y, Yoshigoe S, Nagasaka S, Yajima T, Hisamatsu T, iCREST-CD Study Group

Journal of Crohn's & colitis (Journal of Crohn's and Colitis) 17 ( 8 ) 1193 - 1206 2023.03

ISSN 1873-9946

Background and Aims: Perianal lesion is a refractory phenotype of Crohn's disease [CD] with significantly diminished quality of life. We evaluated the clinical characteristics of perianal lesions in newly diagnosed CD patients and the impact of perianal lesions on the quality of life in Japanese patients with CD. Methods: Patients newly diagnosed with CD after June 2016 were included between December 2018 and June 2020 from the Inception Cohort Registry Study of Patients with CD [iCREST-CD]. Results: Perianal lesions were present in 324 [48.2%] of 672 patients with newly diagnosed CD; 71.9% [233/324] were male. The prevalence of perianal lesions was higher in patients aged <40 years vs ≥40 years, and it decreased with age. Perianal fistula [59.9%] and abscess [30.6%] were the most common perianal lesions. In multivariate analyses, male sex, age <40 years and ileocolonic disease location were significantly associated with a high prevalence of perianal lesions, whereas stricturing behaviour and alcohol intake were associated with low prevalence. Fatigue was more frequent [33.3% vs 21.6%] while work productivity and activity impairment-work time missed [36.3% vs 29.5%] and activity impairment [51.9% vs 41.1%] were numerically higher in patients with than those without perianal lesions. Conclusions: At the time of CD diagnosis, approximately half of the patients had perianal lesions; perianal abscesses and perianal fistulas were the most common. Young age, male sex, disease location and behaviour were significantly associated with the presence of perianal lesions. The presence of perianal lesion was associated with fatigue and impairment of daily activities. Clinical trials registry: University Hospital Medical Information Network Clinical Trials Registry System [UMIN-CTR, UMIN000032237].

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Risk of venous thromboembolism with a central venous catheter in hospitalized Japanese patients with inflammatory bowel disease: a propensity score-matched cohort study

Aoki Yasuhiro, Kiyohara Hiroki, Mikami Yohei, Nanki Kosaku, Kawaguchi Takaaki, Yoshimatsu Yusuke, Sugimoto Shinya, Sujino Tomohisa, Takabayashi Kaoru, Hosoe Naoki, Ogata Haruhiko, Iwao Yasushi, Kanai Takanori

INTESTINAL RESEARCH (Intestinal Research) 21 ( 3 ) 318 - 327 2023.02

ISSN 1598-9100

Background/Aims: Thromboprophylaxis is recommended for hospitalized patients with inflammatory bowel disease (IBD) in Western countries, although it is selectively administered to high-risk patients in East Asia. A central venous catheter (CVC) is commonly placed in patients with IBD. Although CVC placement is considered a risk factor for venous thromboembolism (VTE), the degree of increased risk in patients with IBD is uncertain. This study aimed to identify the risk of VTE with CVC placement in hospitalized Japanese patients with IBD without thromboprophylaxis. Methods: This retrospective cohort study included patients with ulcerative colitis or Crohn’s disease who were admitted for disease flares at Keio University Hospital between January 2016 and December 2020. Patients who already had thrombosis or were administered any antithrombotic treatment on admission were excluded. VTE development during the hospitalization was surveyed, and VTE risk associated with CVC indwelling was estimated using propensity score matching and inverse probability of treatment weighting analyses. Results: Altogether, 497 hospitalized patients with IBD (ulcerative colitis, 327; Crohn’s disease, 170) were enrolled. VTE developed in 9.30% (12/129) of catheterized patients and in 0.82% (3/368) of non-catheterized patients. The propensity score matching yielded 127 matched pairs of patients. The catheterized group demonstrated higher odds for VTE than the non-catheterized group (odds ratio, 13.15; 95% confidence interval, 1.68–102.70). A similar result was obtained in the inverse probability of treatment weighting analysis (odds ratio, 11.02; 95% confidence interval, 2.64–46.10). Conclusions: CVC placement is a major risk factor for VTE among hospitalized Japanese patients with IBD without thromboprophylaxis.

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Expert consensus on vaccination in patients with inflammatory bowel disease in Japan

Ishige T., Shimizu T., Watanabe K., Arai K., Kamei K., Kudo T., Kunisaki R., Tokuhara D., Naganuma M., Mizuochi T., Murashima A., Inoki Y., Iwata N., Iwama I., Koinuma S., Shimizu H., Jimbo K., Takaki Y., Takahashi S., Cho Y., Nambu R., Nishida D., Hagiwara S.i., Hikita N., Fujikawa H., Hosoi K., Hosomi S., Mikami Y., Miyoshi J., Yagi R., Yokoyama Y., Hisamatsu T.

Journal of Gastroenterology (Journal of Gastroenterology) 58 ( 2 ) 135 - 157 2023.02

ISSN 09441174

Immunosuppressive therapies can affect the immune response to or safety of vaccination in patients with inflammatory bowel disease (IBD). The appropriateness of vaccination should be assessed prior to the initiation of IBD treatment because patients with IBD frequently undergo continuous treatment with immunosuppressive drugs. This consensus was developed to support the decision-making process regarding appropriate vaccination for pediatric and adult patients with IBD and physicians by providing critical information according to the published literature and expert consensus about vaccine-preventable diseases (VPDs) [excluding cervical cancer and coronavirus disease 2019 (COVID-19)] in Japan. This consensus includes 19 important clinical questions (CQs) on the following 4 topics: VPDs (6 CQs), live attenuated vaccines (2 CQs), inactivated vaccines (6 CQs), and vaccination for pregnancy, childbirth, and breastfeeding (5 CQs). These topics and CQs were selected under unified consensus by the members of a committee on intractable diseases with support by a Health and Labour Sciences Research Grant. Physicians should provide necessary information on VPDs to their patients with IBD and carefully manage these patients’ IBD if various risk factors for the development or worsening of VPDs are present. This consensus will facilitate informed and shared decision-making in daily IBD clinical practice.

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Non-cystic fibrosis bronchiectasis (NCFB) is a bronchiolectatic disease characterized by MUC5B-dominated mucus hyperproduction

Asakura, T; Okuda, K; Chen, G; Kato, T; Mikami, Y; Gilmore, R; Cardenas, SMB; Chua, M; Masugi, Y; Noone, P; Ribeiro, CMP; Olivier, K; Hasegawa, N; Randell, S; O'Neal, W; Boucher, R

RESPIROLOGY 28 6 - 7 2023.02

ISSN 1323-7799

Disease activity and treatment patterns of newly diagnosed adult patients with Crohn's disease in Japan: Interim analysis of inception cohort registry study of patients with Crohn's disease (iCREST-CD)

Shinzaki, S; Matsuoka, K; Fujii, T; Okamoto, R; Yamada, A; Kunisaki, R; Matsuura, M; Watanabe, K; Shiga, H; Takatsu, N; Bamba, S; Mikami, Y; Yamamoto, T; Shimoyama, T; Motoya, S; Torisu, T; Kobayashi, T; Ohmiya, N; Saruta, M; Matsuda, K; Matsumoto, T; Nakase, H; Maemoto, A; Murata, Y; Yoshigoe, S; Tsuchiya, H; Hisamatsu, T

JOURNAL OF CROHNS & COLITIS 17 905 - 907 2023.02

ISSN 1873-9946

Dose escalation of oral 5-aminosalicylic acid for ulcerative colitis with Mayo endoscopic subscore of one improves long-term prognosis: a one-year multicentre, open-label, randomized controlled trial.

Aoki, Y; Fukuda, T; Kiyohara, H; Yokoyama, A; Nakazawa, A; Yoshimatsu, Y; Sugimoto, S; Nanki, K; Mikami, Y; Fukuhara, K; Mizuno, S; Sujino, T; Mutaguchi, M; Takabayashi, K; Morohoshi, Y; Hosoda, Y; Ogata, H; Iwao, Y; Naganuma, M; Kanai, T

JOURNAL OF CROHNS & COLITIS 17 548 - 548 2023.02

ISSN 1873-9946

Significance of 5-Aminosalicylic Acid Intolerance in the Clinical Management of Ulcerative Colitis

Mikami Y., Tsunoda J., Suzuki S., Mizushima I., Kiyohara H., Kanai T.

Digestion (Digestion) 104 ( 1 ) 58 - 65 2023.01

ISSN 00122823

Background: Two major types of 5-aminosalicylic acid (5-ASA)-containing preparations, namely, mesalazine/5-ASA and sulfasalazine (SASP), are currently used as first-line therapy for ulcerative colitis. Recent reports show that optimization of 5-ASA therapy is beneficial for both patient outcomes and healthcare costs. Although 5-ASA and SASP have good efficacy and safety profiles, clinicians occasionally encounter patients who develop 5-ASA intolerance. Summary: The most common symptoms of acute 5-ASA intolerance syndrome are exacerbation of diarrhea, fever, and abdominal pain. Patients who discontinue 5-ASA therapy because of intolerance have a higher risk of adverse clinical outcomes, such as hospital admission, colectomy, need for advanced therapies, and loss of response to anti-tumor necrosis factor (TNF) biologics. When patients develop symptoms of 5-ASA intolerance, the clinician should consider changing the type of 5-ASA preparation. Recent genome-wide association studies and meta-analyses have shown that 5-ASA allergy is associated with certain single-nucleotide polymorphisms. Although there are no modalities or biomarkers for diagnosing 5-ASA intolerance, the drug-induced lymphocyte stimulation test can be used to assist in the diagnosis of acute 5-ASA intolerance syndrome with high specificity and low sensitivity. This review presents a general overview of 5-ASA and SASP in the treatment of inflammatory bowel disease and discusses the latest insights into 5-ASA intolerance. Key Messages: 5-ASA is used as first-line therapy for ulcerative colitis. Optimization of 5-ASA may be beneficial for patient outcomes and healthcare systems. Acute 5-ASA intolerance syndrome is characterized by diarrhea, fever, and abdominal pain. Periodic renal function monitoring is recommended for patients receiving 5-ASA.

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D-amino Acids Ameliorate Experimental Colitis and Cholangitis by Inhibiting Growth of Proteobacteria: Potential Therapeutic Role in Inflammatory Bowel Disease

Umeda S., Sujino T., Miyamoto K., Yoshimatsu Y., Harada Y., Nishiyama K., Aoto Y., Adachi K., Hayashi N., Amafuji K., Moritoki N., Shibata S., Sasaki N., Mita M., Tanemoto S., Ono K., Mikami Y., Sasabe J., Takabayashi K., Hosoe N., Suzuki T., Sato T., Atarashi K., Teratani T., Ogata H., Nakamoto N., Shiomi D., Ashida H., Kanai T.

Cellular and Molecular Gastroenterology and Hepatology (Cellular and Molecular Gastroenterology and Hepatology) 16 ( 6 ) 1011 - 1031 2023.01

ISSN 2352-345X

Background & Aims: D-amino acids, the chiral counterparts of protein L-amino acids, were primarily produced and utilized by microbes, including those in the human gut. However, little was known about how orally administered or microbe-derived D-amino acids affected the gut microbial community or gut disease progression. Methods: The ratio of D- to L-amino acids was analyzed in feces and blood from patients with ulcerative colitis (UC) and healthy controls. Also, composition of microbe was analyzed from patients with UC. Mice were treated with D-amino acid in dextran sulfate sodium colitis model and liver cholangitis model. Results: The ratio of D- to L-amino acids was lower in the feces of patients with UC than that of healthy controls. Supplementation of D-amino acids ameliorated UC-related experimental colitis and liver cholangitis by inhibiting growth of Proteobacteria. Addition of D-alanine, a major building block for bacterial cell wall formation, to culture medium inhibited expression of the ftsZ gene required for cell fission in the Proteobacteria Escherichia coli and Klebsiella pneumoniae, thereby inhibiting growth. Overexpression of ftsZ restored growth of E. coli even when D-alanine was present. We found that D-alanine not only inhibited invasion of pathological K. pneumoniae into the host via pore formation in intestinal epithelial cells but also inhibited growth of E. coli and generation of antibiotic-resistant strains. Conclusions: D-amino acids might have potential for use in novel therapeutic approaches targeting Proteobacteria-associated dysbiosis and antibiotic-resistant bacterial diseases by means of their effects on the intestinal microbiota community.

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Usefulness of texture and color enhancement imaging in assessing mucosal healing in patients with ulcerative colitis

Hayashi Y., Takabayashi K., Kato M., Tojo A., Aoki Y., Hagihara Y., Yoshida K., Yoshimatsu Y., Kiyohara H., Sugimoto S., Nanki K., Mikami Y., Sujino T., Mutaguchi M., Kawaguchi T., Hosoe N., Yahagi N., Ogata H., Kanai T.

Gastrointestinal Endoscopy (Gastrointestinal Endoscopy) 97 ( 4 ) 759 - 766.e1 2023

ISSN 00165107

Background and aims: Endoscopic remission is known to be defined as a Mayo endoscopic subscore (MES) of ≤1 in patients with ulcerative colitis (UC). However, some individuals experience relapse even after showing endoscopic remission under white-light imaging (WLI), and no tool exists that can detect these individuals. The aim of this study was to clarify the usefulness of texture and color enhancement imaging (TXI) in the assessment of inflammation in patients with UC. Methods: This was a prospective, single-arm, observational study conducted at a university hospital. From January 2021 to December 2021, 146 UC patients with endoscopic remission were enrolled. Images were evaluated by WLI, TXI, and pathologic evaluation, followed by prognostic studies. The primary endpoint of the study was the cumulative relapse of UC in each TXI score. The secondary endpoints were the association between TXI and pathologic scores, predictors of relapse, and interobserver agreement between the MES and TXI scores. Results: Patients with TXI score 2 had significantly lower UC relapse-free rates than did those with TXI scores 0-1 (log-rank test, P <.01). When pathologic remission was defined as Matts grade ≤2, the rate of pathologic remission decreased significantly with higher TXI scores (P =.01). In multivariate analysis, TXI score 2 was the only risk factor for UC relapse (P <.01; hazard ratio, 4.16; 95% confidence interval, 1.72-10.04). Interobserver agreement on the TXI score was good (κ = 0.597-0.823). Conclusion: TXI can be used to identify populations with poor prognosis in MES 1, for whom treatment intensification has been controversial.

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Divergent roles for STAT4 in shaping differentiation of cytotoxic ILC1 and NK cells during gut inflammation

Scarno G., Mazej J., Laffranchi M., Censo C.D., Mattiola I., Candelotti A.M., Pietropaolo G., Stabile H., Fionda C., Peruzzi G., Brooks S.R., Tsai W.L., Mikami Y., Bernardini G., Gismondi A., Sozzani S., Di Santo J.P., Vosshenrich C.A.J., Diefenbach A., Gadina M., Santoni A., Sciumè G.

Proceedings of the National Academy of Sciences of the United States of America (Proceedings of the National Academy of Sciences of the United States of America) 120 ( 40 ) e2306761120 2023

ISSN 00278424

Natural killer (NK) cells and type 1 innate lymphoid cells (ILC1) require signal transducer and activator of transcription 4 (STAT4) to elicit rapid effector responses and protect against pathogens. By combining genetic and transcriptomic approaches, we uncovered divergent roles for STAT4 in regulating effector differentiation of these functionally related cell types. Stat4 deletion in Ncr1-expressing cells led to impaired NK cell terminal differentiation as well as to an unexpected increased generation of cytotoxic ILC1 during intestinal inflammation. Mechanistically, Stat4-deficient ILC1 exhibited upregulation of gene modules regulated by STAT5 in vivo and an aberrant effector differentiation upon in vitro stimulation with IL-2, used as a prototypical STAT5 activator. Moreover, STAT4 expression in NCR+ innate lymphocytes restrained gut inflammation in the dextran sulfate sodium-induced colitis model limiting pathogenic production of IL-13 from adaptive CD4+ T cells in the large intestine. Collectively, our data shed light on shared and distinctive mechanisms of STAT4-regulated transcriptional control in NK cells and ILC1 required for intestinal inflammatory responses.

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Single-cell transcriptomics of human gut T cells identifies cytotoxic CD4+CD8A+ T cells related to mouse CD4 cytotoxic T cells

Tanemoto S., Sujino T., Miyamoto K., Moody J., Yoshimatsu Y., Ando Y., Koya I., Harada Y., Tojo A.O., Ono K., Hayashi Y., Takabayashi K., Okabayashi K., Teratani T., Mikami Y., Nakamoto N., Hosoe N., Ogata H., Hon C.C., Shin J.W., Kanai T.

Frontiers in Immunology (Frontiers in Immunology) 13 977117 2022.10

ISSN 1664-3224

Cytotoxic CD4+ T cells (CD4-CTLs) show the presence of cytolytic granules, which include the enzymes granzyme and perforin. The cells have a pathogenic and protective role in various diseases, including cancer, viral infection, and autoimmune disease. In mice, cytotoxic CD4+ T cells express CD8αα+ and reside in the intestine (mouse CD4+CTLs; mCD4-CTLs). The population of cytotoxic CD4+ T cells in the human intestine is currently unknown. Moreover, it is unclear how cytotoxic CD4 T cells change in patients with inflammatory bowel disease (IBD). Here, we aimed to identify cytotoxic CD4+ T cells in the human intestine and analyze the characteristics of the population in patients with IBD using single-cell RNA-seq (scRNA-seq). In CD4+ T cells, granzyme and perforin expression was high in humanMAIT (hMAIT) cells and hCD4+CD8A+ T cell cluster. Both CD4 and CD8A were expressed in hTreg, hMAIT, and hCD4+CD8A+ T cell clusters. Next we performed fast gene set enrichment analysis to identify cell populations that showed homology to mCD4CTLs. The analysis identified the hCD4+CD8A+ T cell cluster (hCTL-like population; hCD4-CTL) similar to mouse CTLs. The percentage of CD4+CD8A+ T cells among the total CD4+ T cells in the inflamed intestine of the patients with Crohn’s disease was significantly reduced compared with that in the noninflamed intestine of the patients. In summary, we identified cytotoxic CD4+CD8+ T cells in the small intestine of humans. The integration of the mouse and human sc-RNA-seq data analysis highlight an approach to identify human cell populations related to mouse cell populations, which may help determine the functional properties of several human cell populations in mice.

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Enrichment of type I interferon signaling in colonic group 2 innate lymphoid cells in experimental colitis

Irie E., Ishihara R., Mizushima I., Hatai S., Hagihara Y., Takada Y., Tsunoda J., Iwata K., Matsubara Y., Yoshimatsu Y., Kiyohara H., Taniki N., Sujino T., Takabayashi K., Hosoe N., Ogata H., Teratani T., Nakamoto N., Mikami Y., Kanai T.

Frontiers in Immunology (Frontiers in Immunology) 13 982827 2022.10

ISSN 1664-3224

Group 2 innate lymphoid cells (ILC2s) serve as frontline defenses against parasites. However, excluding helminth infections, it is poorly understood how ILC2s function in intestinal inflammation, including inflammatory bowel disease. Here, we analyzed the global gene expression of ILC2s in healthy and colitic conditions and revealed that type I interferon (T1IFN)-stimulated genes were up-regulated in ILC2s in dextran sodium sulfate (DSS)-induced colitis. The enhancement of T1IFN signaling in ILC2s in DSS-induced colitis was correlated with the downregulation of cytokine production by ILC2s, such as interleukin-5. Blocking T1IFN signaling during colitis resulted in exaggeration of colitis in both wild-type and Rag2-deficient mice. The exacerbation of colitis induced by neutralization of T1IFN signaling was accompanied by reduction of amphiregulin (AREG) in ILC2s and was partially rescued by exogenous AREG treatment. Collectively, these findings show the potential roles of T1IFN in ILC2s that contribute to colitis manifestation.

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Severe graft-versus-host disease-like enterocolitis accompanied with cytomegalovirus-reactivation in drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms

Takamiyagi S., Iriki H., Asahina Y., Furuichi Y., Funakoshi T., Ichikawa M., Mikami Y., Okita H., Sakiyama T., Inazumi T., Amagai M., Takahashi H.

Journal of Dermatology (Journal of Dermatology) 49 ( 8 ) 796 - 799 2022.08

ISSN 03852407

Drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe drug adverse reaction with skin eruption and visceral organ involvement. The characteristic clinical features of DIHS/DRESS are reactivation of human herpesviruses (HHV) and the development of autoimmune diseases, but their pathogenesis and associations are not yet understood. Here, we report a 66-year-old man who presented with fever, generalized erythema, diffuse lymphadenopathy, and diarrhea after 3 weeks of treatment with zonisamide. Reactivation of HHV-6 and cytomegalovirus (CMV) was detected during the clinical course. The patient was diagnosed with DIHS/DRESS and treated with systemic prednisolone, i.v. immunoglobulin therapy, and ganciclovir. However, severe enterocolitis persisted for 6 months. A series of examinations revealed features of both CMV enterocolitis, as indicated by identification of a few CMV-positive cells on immunohistochemical analysis, and graft-versus-host disease (GVHD)-like enterocolitis indicated by orange-peel appearance on endoscopic examination and histopathological loss of goblet cells. Intractable enterocolitis continued and the patient finally died of pneumonia. An autoimmune predisposition in DIHS/DRESS patients in combination with CMV reactivation was considered to trigger the severe enterocolitis of this case that showed GVHD-like features of the gastrointestinal tract. GVHD-like organ damage is a pathological condition rarely observed in DIHS/DRESS but should be recognized as one of the most severe complications of the disease.

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Neuroimmune crosstalk in the gut and liver

Teratani Toshiaki, Mikami Yohei, Kanai Takanori

INTERNATIONAL IMMUNOLOGY (International immunology) 34 ( 9 ) 475 - 484 2022.07

ISSN 0953-8178

It has long been assumed that the nervous system exerts distinct effects on immune functions, given the large number of immune disorders that are affected by mental stress. In fact, many different immune cells have been shown to possess a wide variety of neurotransmitter receptors and receive signals from various neurotransmitters, including acetylcholine and noradrenaline. Compared with the findings on local neuroimmune interactions, limited experimental techniques have so far failed to capture a comprehensive overview of neuroimmune interactions between distant organs and the autonomic nervous system in vivo, and the molecular mechanisms underlying local immune regulation of the nervous system have long remained unclear. However, the recent rapid progress in genetic recombination, microscopy and single-cell analysis has deepened our understanding of the anatomical and physiological functions of peripheral nerves at each organ to which they belong. Furthermore, the development of optogenetic and chemogenetic methods has enabled the artificial modulation of specific neuronal activities, and there has been remarkable progress in elucidation of the interaction between nerves and immune cells in vivo, particularly in barrier organs such as the gastrointestinal tract, respiratory tract and skin. This review focuses on the immunoregulatory mechanisms governed by the autonomic nervous system and outlines the latest findings in the regulation of enteric and hepatic immunity by the nervous system.

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Efficacy of Calcineurin Inhibitors for Induction of Remission in Intestinal Behçet's Disease

Kawaguchi T., Fukata M., Omori T., Kiyohara H., Sugimoto S., Nanki K., Sujino T., Mikami Y., Kanai T.

Crohn's and Colitis 360 (Crohn's and Colitis 360) 4 ( 3 ) otac017 2022.07

Background: The efficacy of calcineurin inhibitors (CNIs) for induction of remission in intestinal Behçet's disease (intestinal BD) has not been explored. Methods: A multicenter retrospective case series study of patients with active intestinal BD treated with CNIs (cyclosporin and tacrolimus) was conducted. Results: Of 16 patients, 12 (75%) showed a clinical response and 5 (31.3%) achieved clinical remission after 2 weeks of CNI treatment. Similar efficacy of CNIs was observed even in 7 patients refractory to antitumor necrosis factor-alpha therapies. Endoscopic improvement was observed in 11 of 12 patients. Conclusions: CNIs may be promising treatment options for refractory intestinal BD.

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Heterogeneity of ILC2s in the Intestine; Homeostasis and Pathology

Sunaga S., Tsunoda J., Teratani T., Mikami Y., Kanai T.

Frontiers in Immunology (Frontiers in Immunology) 13 867351 2022.05

ISSN 1664-3224

Group 2 innate lymphoid cells (ILC2s) were identified in 2010 as a novel lymphocyte subset lacking antigen receptors, such as T-cell or B-cell receptors. ILC2s induce local immune responses characterized by producing type 2 cytokines and play essential roles for maintaining tissue homeostasis. ILC2s are distributed across various organs, including the intestine where immune cells are continuously exposed to external antigens. Followed by luminal antigen stimulation, intestinal epithelial cells produce alarmins, such as IL-25, IL-33, and thymic stromal lymphopoietin, and activate ILC2s to expand and produce cytokines. In the context of parasite infection, the tuft cell lining in the epithelium has been revealed as a dominant source of intestinal IL-25 and possesses the capability to regulate ILC2 homeostasis. Neuronal systems also regulate ILC2s through neuropeptides and neurotransmitters, and interact with ILC2s bidirectionally, a process termed “neuro-immune crosstalk”. Activated ILC2s produce type 2 cytokines, which contribute to epithelial barrier function, clearance of luminal antigens and tissue repair, while ILC2s are also involved in chronic inflammation and tissue fibrosis. Recent studies have shed light on the contribution of ILC2s to inflammatory bowel diseases, mainly comprising ulcerative colitis and Crohn’s disease, as defined by chronic immune activation and inflammation. Modern single-cell analysis techniques provide a tissue-specific picture of ILC2s and their roles in regulating homeostasis in each organ. Particularly, single-cell analysis helps our understanding of the uniqueness and commonness of ILC2s across tissues and opens the novel research area of ILC2 heterogeneity. ILC2s are classified into different phenotypes depending on tissue and phase of inflammation, mainly inflammatory and natural ILC2 cells. ILC2s can also switch phenotype to ILC1- or ILC3-like subsets. Hence, recent studies have revealed the heterogeneity and plasticity of ILC2, which indicate dynamicity of inflammation and the immune system. In this review, we describe the regulatory mechanisms, function, and pathological roles of ILC2s in the intestine.

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Aryl hydrocarbon receptor signals in epithelial cells govern the recruitment and location of Helios+ Tregs in the gut

Yoshimatsu Y., Sujino T., Miyamoto K., Harada Y., Tanemoto S., Ono K., Umeda S., Yoshida K., Teratani T., Suzuki T., Mikami Y., Nakamoto N., Sasaki N., Takabayashi K., Hosoe N., Ogata H., Sawada K., Imamura T., Yoshimura A., Kanai T.

Cell Reports (Cell Reports) 39 ( 6 ) 110773 2022.05

ISSN 2211-1247

CD4+Foxp3+ regulatory T cells (Tregs) are essential for homeostasis in the colon, but the mechanism by which local environmental cues determine the localization of colonic Tregs is unclear. Here, we administer indigo naturalis (IN), a nontoxic phytochemical aryl hydrocarbon receptor (AhR) agonist used for treating patients with ulcerative colitis (UC) in Asia, and we show that IN increases Helios+ Tregs and MHC class II+ epithelial cells (ECs) in the colon. Interactions between Tregs and MHC class II+ ECs occur mainly near the crypt bottom in the steady state, whereas Tregs dramatically increase and shift toward the crypt top following IN treatment. Moreover, the number of CD25+ T cells is increased near the surface of ECs in IN-treated UC patients compared with that in patients treated with other therapies. We also highlight additional AhR-signaling mechanisms in intestinal ECs that determine the accumulation and localization of Helios+ Tregs in the colon.

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Intracellular metabolic adaptation of intraepithelial CD4+CD8αα+ T lymphocytes

Harada Y., Sujino T., Miyamoto K., Nomura E., Yoshimatsu Y., Tanemoto S., Umeda S., Ono K., Mikami Y., Nakamoto N., Takabayashi K., Hosoe N., Ogata H., Ikenoue T., Hirao A., Kubota Y., Kanai T.

iScience (iScience) 25 ( 4 ) 104021 2022.04

Intestinal intraepithelial lymphocytes (IELs), the first line of defense against microbial and dietary antigens, are classified as natural or induced based on their origin and receptor expression. Induced CD4+CD8αα+TCRβ+ T cells (double positive, DPIELs) originated from CD4+CD8α−TCRβ+ T cells (single positive, SPIELs) increase with aging. However, the metabolic requirements and the metabolic-related genes in IEL development remain unclear. We determined that the intraepithelial compartment is hypoxic in the presence of microbes and DPIELs increased more than natural IELs in this location. Moreover, DPIELs consumed less oxygen and glucose and exhibited unique alterations in mitochondria. Using inhibitors and genetically modified mice, we revealed that DPIELs adapt to their surrounding oxygen-deprived environment in peripheral tissues by modulating specific genes, including hypoxia-inducible factor, mammalian target of rapamycin complexes (mTORC), phosphorylated ribosomal protein S6 (pS6), and other glycolytic factors. Our findings provide valuable insight into the metabolic properties of IELs.

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