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Papers - Hase, Koji

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Protective effect of mesenchymal stromal cells in diabetic nephropathy: the In vitro and In vivo role of the M-Sec-tunneling nanotubes

Barutta F., Corbetta B., Bellini S., Gambino R., Bruno S., Kimura S., Hase K., Ohno H., Gruden G.

Clinical Science 138 ( 23 ) 1537 - 1559 2024.12

Research paper (scientific journal), Accepted

Mitochondrial dysfunction plays an important role in the development of podocyte injury in diabetic nephropathy (DN). Tunnelling nanotubes (TNTs) are long channels that connect cells and allow organelle exchange. Mesenchymal stromal cells (MSCs) can transfer mitochondria to other cells through the M-Sec-TNTs system. However, it remains unexplored whether MSCs can form heterotypic TNTs with podocytes, thereby enabling the replacement of diabetes-damaged mitochondria. In this study, we analysed TNT formation, mitochondrial transfer, and markers of cell injury in podocytes that were pre-exposed to diabetes-related insults and then co-cultured with diabetic or non-diabetic MSCs. Furthermore, to assess the in vivo relevance, we treated DN mice with exogenous MSCs, either expressing or lacking M-Sec, carrying fluorescent-tagged mitochondria. MSCs formed heterotypic TNTs with podocytes, allowing mitochondrial transfer, via a M-Sec-dependent mechanism. This ameliorated mitochondrial function, nephrin expression, and reduced apoptosis in recipient podocytes. However, MSCs isolated from diabetic mice failed to confer cytoprotection due to Miro-1 down-regulation. In experimental DN, treatment with exogenous MSCs significantly improved DN, but no benefit was observed in mice treated with MSCs lacking M-Sec. Mitochondrial transfer from exogenous MSCs to podocytes occurred in vivo in a M-Sec-dependent manner. These findings demonstrate that the M-Sec-TNT-mediated transfer of mitochondria from healthy MSCs to diabetes-injured podocytes can ameliorate podocyte damage. Moreover, M-Sec expression in exogenous MSCs is essential for providing renoprotection in vivo in experimental DN.

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Intestinal epithelium dysfunctions cause IgA deposition in the kidney glomeruli of intestine-specific Ap1m2-deficient mice

Kinashi Y., Tanaka K., Kimura S., Hirota M., Komiyama S., Shindo T., Hashiguchi A., Takahashi D., Shibata S., Karaki S.I., Ohno H., Hase K.

EBioMedicine 106 2024.08

Research paper (scientific journal), Last author, Corresponding author, Accepted

Background: Intestinal epithelial cells (IECs) serve as robust barriers against potentially hostile luminal antigens and commensal microbiota. Epithelial barrier dysfunction enhances intestinal permeability, leading to leaky gut syndrome (LGS) associated with autoimmune and chronic inflammatory disorders. However, a causal relationship between LGS and systemic disorders remains unclear. Ap1m2 encodes clathrin adaptor protein complex 1 subunit mu 2, which facilitates polarized protein trafficking toward the basolateral membrane and contributes to the establishment of epithelial barrier functions. Methods: We generated IEC-specific Ap1m2-deficient (Ap1m2ΔIEC) mice with low intestinal barrier integrity as an LSG model and examined the systemic impact. Findings: Ap1m2ΔIEC mice spontaneously developed IgA nephropathy (IgAN)-like features characterized by the deposition of IgA–IgG immune complexes and complement factors in the kidney glomeruli. Ap1m2 deficiency markedly enhanced aberrantly glycosylated IgA in the serum owing to downregulation and mis-sorting of polymeric immunoglobulin receptors in IECs. Furthermore, Ap1m2 deficiency caused intestinal dysbiosis by attenuating IL-22-STAT3 signaling. Intestinal dysbiosis contributed to the pathogenesis of IgAN because antibiotic treatment reduced aberrantly glycosylated IgA production and renal IgA deposition in Ap1m2ΔIEC mice. Interpretation: IEC barrier dysfunction and subsequent dysbiosis by AP-1B deficiency provoke IgA deposition in the mouse kidney. Our findings provide experimental evidence of a pathological link between LGS and IgAN. Funding: AMED, AMED-CREST, JSPS Grants-in-Aid for Scientific Research, JST CREST, Fuji Foundation for Protein Research, and Keio University Program for the Advancement of Next Generation Research Projects.

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Sugar and arginine facilitate oral tolerance by ensuring the functionality of tolerogenic immune cell subsets in the intestine

Nagai M., Okawa T., Nakata K., Takahashi D., Miyajima R., Shiratori H., Yamanaka D., Nakamura A., Oyama C., Takahashi S.I., Toyama-Sorimachi N., Suzuki K., Ohashi W., Dohi T., Kawamura Y.I., Hase K.

Cell Reports 43 ( 7 ) 2024.07

Research paper (scientific journal), Last author, Corresponding author, Accepted

Although oral tolerance is a critical system in regulating allergic disorders, the mechanisms by which dietary factors regulate the induction and maintenance of oral tolerance remain unclear. To address this, we explored the differentiation and function of various immune cells in the intestinal immune system under fasting and ad libitum-fed conditions before oral ovalbumin (OVA) administration. Fasting mitigated OVA-specific Treg expansion, which is essential for oral tolerance induction. This abnormality mainly resulted from functional defects in the CX3CR1+ cells responsible for the uptake of luminal OVA and reduction of tolerogenic CD103+ dendritic cells. Eventually, fasting impaired the preventive effect of oral OVA administration on asthma and allergic rhinitis development. Specific food ingredients, namely carbohydrates and arginine, were indispensable for oral tolerance induction by activating glycolysis and mTOR signaling. Overall, prior food intake and nutritional signals are critical for maintaining immune homeostasis by inducing tolerance to ingested food antigens.

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A purified diet affects intestinal epithelial proliferation and barrier functions through gut microbial alterations

Shiratori H., Hattori K.M., Nakata K., Okawa T., Komiyama S., Kinashi Y., Kabumoto Y., Kaneko Y., Nagai M., Shindo T., Moritoki N., Kawamura Y.I., Dohi T., Takahashi D., Kimura S., Hase K.

International Immunology 36 ( 5 ) 223 - 240 2024.05

ISSN 09538178

The gut microbiota plays a crucial role in maintaining epithelial barrier function. Although multiple studies have demonstrated the significance of dietary factors on the gut microbiota and mucosal barrier function, the impact of a purified diet, which has long been used in various animal experiments, on intestinal homeostasis remains to be elucidated. Here, we compared the impact of two different types of diets, a crude diet and an AIN-93G-formula purified diet, on epithelial integrity and the gut microbiota. Purified diet-fed mice exhibited shorter villi and crypt lengths and slower epithelial turnover, particularly in the ileum. In addition, antimicrobial products, including REG3γ, were substantially decreased in purified diet-fed mice. Purified diet feeding also suppressed α1,2-fucosylation on the epithelial surface. Furthermore, the purified diet induced metabolic rewiring to fatty acid oxidation and ketogenesis. 16S ribosomal RNA gene sequencing of the ileal contents and mucus layer revealed distinct gut microbiota compositions between the purified and crude diet-fed mice. Purified diet feeding reduced the abundance of segmented filamentous bacteria (SFB), which potently upregulate REG3γand fucosyltransferase 2 (Fut2) by stimulating group 3 innate lymphoid cells (ILC3s) to produce IL-22. These observations illustrate that the intake of a crude diet secures epithelial barrier function by facilitating SFB colonization, whereas a purified diet insufficiently establishes the epithelial barrier, at least partly owing to the loss of SFB. Our data suggest that the influence of purified diets on the epithelial barrier integrity should be considered in experiments using purified diets.

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MZB1-mediated IgA secretion suppresses the development and progression of colorectal cancer triggered by gut inflammation.

Tang Y, Feng X, Cui C, Yu M, Wen Z, Luan Y, Dong L, Hu Z, Zhang R, Liu J, Shinkura R, Hase K, Lu Q, Wang JY.

Mucosal Immunol. 17 ( 3 ) 450 - 460 2023.12

Research paper (scientific journal), Accepted, ISSN 19330219

Colorectal cancer (CRC) ranks among the top causes of mortality globally. Gut inflammation is one crucial risk factor that augments CRC development since patients suffering from inflammatory bowel disease have an increased incidence of CRC. The role of immunoglobulin (Ig)A in maintaining gut homeostasis and preventing inflammation has been well established. Our earlier work demonstrated that the marginal zone and B1 cell-specific protein (MZB1) promotes gut IgA secretion and its absence results in pronounced dextran sulfate sodium salt (DSS)-induced colitis. In the present study, we explored the role of MZB1 in CRC development using the azoxymethane (AOM)/DSS-induced CRC model. We observed an increase in both the number and size of the tumor nodules in Mzb1−/− mice compared with Mzb1+/+ mice. The increase in CRC development and progression in Mzb1−/− mice was associated with reduced intestinal IgA levels, altered gut flora, and more severe gut and systemic inflammation. Oral administration of the monoclonal IgA, W27, alleviated both the gut inflammation and AOM/DSS-induced CRC. Notably, cohousing Mzb1+/+ and Mzb1−/− mice from the 10th day after birth led to similar CRC development. Our findings underscore the pivotal role of MZB1-mediated IgA secretion in suppressing the onset and progression of CRC triggered by gut inflammation. Moreover, our study highlights the profound impact of microbiota composition, modulated by gut IgA levels, on gut inflammation. Nonetheless, establishing a direct correlation between the severity of colitis and subsequent CRC development and the presence or absence of a particular microbiota is challenging.

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α-Glucosidase inhibitors boost gut immunity by inducing IgA responses in Peyer's patches.

Hattori-Muroi K, Naganawa-Asaoka H, Kabumoto Y, Tsukamoto K, Fujisaki Y, Fujimura Y, Komiyama S, Kinashi Y, Kato M, Sato S, Takahashi D, Hase K.

Front Immunol. 14 1277637 2023.11

Research paper (scientific journal), Last author, Corresponding author, Accepted

Peyer’s patches (PPs) are specialized gut-associated lymphoid tissues that initiate follicular helper T (Tfh)-mediated immunoglobulin A (IgA) response to luminal antigens derived from commensal symbionts, pathobionts, and dietary sources. IgA-producing B cells migrate from PPs to the small intestinal lamina propria and secrete IgA across the epithelium, modulating the ecological balance of the commensal microbiota and neutralizing pathogenic microorganisms. α-glucosidase inhibitors (α-GIs) are antidiabetic drugs that inhibit carbohydrate digestion in the small intestinal epithelium, leading to alterations in the commensal microbiota composition and metabolic activity. The commensal microbiota and IgA responses exhibit bidirectional interactions that modulate intestinal homeostasis and immunity. However, the effect of α-GIs on the intestinal IgA response remains unclear. We investigated whether α-GIs affect IgA responses by administering voglibose and acarbose to mice via drinking water. We analyzed Tfh cells, germinal center (GC) B cells, and IgA-producing B cells in PPs by flow cytometry. We also assessed pathogen-specific IgA responses. We discovered that voglibose and acarbose induced Tfh cells, GCB cells, and IgA-producing B cells in the PPs of the proximal small intestine in mice. This effect was attributed to the modification of the microbiota rather than a shortage of monosaccharides. Furthermore, voglibose enhanced secretory IgA (S-IgA) production against attenuated Salmonella Typhimurium. Our findings reveal a novel mechanism by which α-GIs augment antigen-specific IgA responses by stimulating Tfh-GCB responses in PPs, and suggest a potential therapeutic application as an adjuvant for augmenting mucosal vaccines.

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Safe and efficient oral allergy immunotherapy using one-pot-prepared mannan-coated allergen nanoparticles.

Li S, Toriumi H, Takahashi D, Kamasaki T, Fujioka Y, Nagatoishi S, Li J, Liu Y, Hosokawa T, Tsumoto K, Ohba Y, Katayama Y, Murakami D, Hase K, Mori T.

Biomaterials 303 122381 2023.10

Research paper (scientific journal), Corresponding author, Accepted, ISSN 01429612

Allergen immunotherapy (AIT) is the only curative treatment for allergic diseases. However, AIT has many disadvantages related to efficiency, safety, long-term duration, and patient compliance. Dendritic cells (DCs) have an important role in antigen-specific tolerance induction; thus, DC-targeting strategies to treat allergies such as glutaraldehyde crosslinked antigen to mannoprotein (MAN) have been established. However, glutaraldehyde crosslinking may reduce the antigen presentation efficiency of DCs. To overcome this, we developed a MAN-coated ovalbumin (OVA) nanoparticle (MDO), which uses intermolecular disulfide bond to crosslink OVA and MAN. MDO effectively targeted DCs resulting in tolerogenic DCs, and promoted higher antigen presentation efficiency by DCs compared with OVA or glutaraldehyde crosslinked nanoparticles. In vitro and in vivo experiments showed that DCs exposed to MDO induced Treg cells. Moreover, MDO had low reactivity with anti-OVA antibodies and did not induce anaphylaxis in allergic mice, demonstrating its high safety profile. In a mouse model of allergic asthma, MDO had significant preventative and therapeutic effects when administered orally or subcutaneously. Therefore, MDO represents a promising new approach for the efficient and safe treatment of allergies.

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Gut microbiota-derived lipid metabolites facilitate regulatory T cell differentiation

4 Shiratori H, Oguchi H, Isobe Y, Han KH, Sen A, Yakebe K, Takahashi D, Fukushima M, Arita M, Hase K.

Sci. Rep. 13 ( 1 ) 8903 2023.06

Research paper (scientific journal), Last author, Corresponding author, Accepted

Commensal bacteria-derived metabolites are critical in regulating the host immune system. Although the impact of gut microbiota-derived hydrophilic metabolites, such as short-chain fatty acids, on immune cell functions and development has been well documented, the immunomodulatory effects of gut microbiota-derived lipids are still of interest. Here, we report that lipid extracts from the feces of specific-pathogen-free (SPF), but not germ-free (GF), mice showed regulatory T (Treg)-cell-inducing activity. We conducted RP-HPLC-based fractionation and liquid chromatography–tandem mass spectrometry (LC–MS/MS)-based lipidome profiling and identified two bioactive lipids, 9,10-dihydroxy-12Z-octadecenoic acid (9,10-DiHOME) and all-trans retinoic acid (atRA), with Treg-inducing activity in vitro. The luminal abundance of 9,10-DiHOME in the large intestine was significantly decreased by dextran sulfate sodium (DSS)-induced colitis, indicating that 9,10-DiHOME may be a potential biomarker of colitis. These observations implied that commensal bacteria-derived lipophilic metabolites might contribute to Treg development in the large intestine.

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Dysfunction of Foxp3<sup>+</sup> Regulatory T Cells Induces Dysbiosis of Gut Microbiota via Aberrant Binding of Immunoglobulins to Microbes in the Intestinal Lumen

Koshida K., Ito M., Yakabe K., Takahashi Y., Tai Y., Akasako R., Kimizuka T., Takano S., Sakamoto N., Haniuda K., Ogawa S., Kimura S., Kim Y.G., Hase K., Harada Y.

International Journal of Molecular Sciences 24 ( 10 ) 2023.05

ISSN 16616596

Foxp3+ regulatory T (Treg) cells prevent excessive immune responses against dietary antigens and commensal bacteria in the intestine. Moreover, Treg cells contribute to the establishment of a symbiotic relationship between the host and gut microbes, partly through immunoglobulin A. However, the mechanism by which Treg cell dysfunction disturbs the balanced intestinal microbiota remains unclear. In this study, we used Foxp3 conditional knockout mice to conditionally ablate the Foxp3 gene in adult mice and examine the relationship between Treg cells and intestinal bacterial communities. Deletion of Foxp3 reduced the relative abundance of Clostridia, suggesting that Treg cells have a role in maintaining Treg-inducing microbes. Additionally, the knockout increased the levels of fecal immunoglobulins and immunoglobulin-coated bacteria. This increase was due to immunoglobulin leakage into the gut lumen as a result of loss of mucosal integrity, which is dependent on the gut microbiota. Our findings suggest that Treg cell dysfunction leads to gut dysbiosis via aberrant antibody binding to the intestinal microbes.

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Dietary iodine attenuates allergic rhinitis by inducing ferroptosis in activated B cells.

Nakamura Y, Fuse Y, Komiyama S, Nagatake T, Kunisawa J, Hase K.

Sci. Rep. 13 ( 1 ) 5398 2023.04

Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted

Iodine-containing formulations have been widely used to treat iodine deficiency and as antiseptics. Lecithin-bound iodine (LBI) has been approved to treat allergic diseases in Japan; however, its underlying mechanism remains unknown. In this study, we show that LBI ameliorated disease symptoms in an ovalbumin (OVA)-induced allergic rhinitis mouse model. LBI suppressed OVA-specific IgE production by attenuating germinal center (GC) reaction in the draining lymph nodes. The antiallergic effect of LBI is most likely attributed to increased serum iodine levels but not thyroid hormone levels. In vitro treatment of activated B cells with potassium iodide induced ferroptosis by increasing intracellular reactive oxygen species (ROS) and ferrous iron in a concentration-dependent manner. Accordingly, LBI diets increased ROS levels in GC B cells of the draining lymph nodes. This study suggests that iodine directly promotes ferroptosis in activated B cells and attenuates GC reactions, leading to the alleviation of allergic symptoms.

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Protective effect of the tunneling nanotube-TNFAIP2/M-sec system on podocyte autophagy in diabetic nephropathy.

6 Barutta F, Bellini S, Kimura S, Hase K, Corbetta B, Corbelli A, Fiordaliso F, Bruno S, Biancone L, Barreca A, Papotti MG, Hirsh E, Martini M, Gambino R, Durazzo M, Ohno H, Gruden G.

Autophagy 19 ( 2 ) 505 - 524 2023.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 15548627

Podocyte injury leading to albuminuria is a characteristic feature of diabetic nephropathy (DN). Hyperglycemia and advanced glycation end products (AGEs) are major determinants of DN. However, the underlying mechanisms of podocyte injury remain poorly understood. The cytosolic protein TNFAIP2/M-Sec is required for tunneling nanotubes (TNTs) formation, which are membrane channels that transiently connect cells, allowing organelle transfer. Podocytes express TNFAIP2 and form TNTs, but the potential relevance of the TNFAIP2-TNT system in DN is unknown. We studied TNFAIP2 expression in both human and experimental DN and the renal effect of tnfaip2 deletion in streptozotocin-induced DN. Moreover, we explored the role of the TNFAIP2-TNT system in podocytes exposed to diabetes-related insults. TNFAIP2 was overexpressed by podocytes in both human and experimental DN and exposre of podocytes to high glucose and AGEs induced the TNFAIP2-TNT system. In diabetic mice, tnfaip2 deletion exacerbated albuminuria, renal function loss, podocyte injury, and mesangial expansion. Moreover, blockade of the autophagic flux due to lysosomal dysfunction was observed in diabetes-injured podocytes both in vitro and in vivo and exacerbated by tnfaip2 deletion. TNTs allowed autophagosome and lysosome exchange between podocytes, thereby ameliorating AGE-induced lysosomal dysfunction and apoptosis. This protective effect was abolished by tnfaip2 deletion, TNT inhibition, and donor cell lysosome damage. By contrast, Tnfaip2 overexpression enhanced TNT-mediated transfer and prevented AGE-induced autophagy and lysosome dysfunction and apoptosis. In conclusion, TNFAIP2 plays an important protective role in podocytes in the context of DN by allowing TNT-mediated autophagosome and lysosome exchange and may represent a novel druggable target. Abbreviations: AGEs: advanced glycation end products; AKT1: AKT serine/threonine kinase 1; AO: acridine orange; ALs: autolysosomes; APs: autophagosomes; BM: bone marrow; BSA: bovine serum albumin; CTSD: cathepsin D; DIC: differential interference contrast; DN: diabetic nephropathy; FSGS: focal segmental glomerulosclerosis; HG: high glucose; KO: knockout; LAMP1: lysosomal-associated membrane protein 1; LMP: lysosomal membrane permeabilization; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; PI3K: phosphoinositide 3-kinase; STZ: streptozotocin; TNF: tumor necrosis factor; TNFAIP2: tumor necrosis factor, alpha-induced protein 2; TNTs: tunneling nanotubes; WT: wild type.

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Medium-chain fatty acids suppress lipotoxicity-induced hepatic fibrosis via the immunomodulating receptor GPR84

Ohue-Kitano R., Nonaka H., Nishida A., Masujima Y., Takahashi D., Ikeda T., Uwamizu A., Tanaka M., Kohjima M., Igarashi M., Katoh H., Tanaka T., Inoue A., Suganami T., Hase K., Ogawa Y., Aoki J., Kimura I.

JCI Insight (JCI Insight) 8 ( 2 ) 2023.01

Medium-chain triglycerides (MCTs), which consist of medium-chain fatty acids (MCFAs), are unique forms of dietary fat with various health benefits. G protein–coupled 84 (GPR84) acts as a receptor for MCFAs (especially C10:0 and C12:0); however, GPR84 is still considered an orphan receptor, and the nutritional signaling of endogenous and dietary MCFAs via GPR84 remains unclear. Here, we showed that endogenous MCFA-mediated GPR84 signaling protected hepatic functions from diet-induced lipotoxicity. Under high-fat diet (HFD) conditions, GPR84-deficient mice exhibited nonalcoholic steatohepatitis (NASH) and the progression of hepatic fibrosis but not steatosis. With markedly increased hepatic MCFA levels under HFD, GPR84 suppressed lipotoxicity-induced macrophage overactivation. Thus, GPR84 is an immunomodulating receptor that suppresses excessive dietary fat intake–induced toxicity by sensing increases in MCFAs. Additionally, administering MCTs, MCFAs (C10:0 or C12:0, but not C8:0), or GPR84 agonists effectively improved NASH in mouse models. Therefore, exogenous GPR84 stimulation is a potential strategy for treating NASH.

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Dietary-protein sources modulate host susceptibility to Clostridioides difficile infection through the gut microbiota

Yakabe K., Higashi S., Akiyama M., Mori H., Murakami T., Toyoda A., Sugiyama Y., Kishino S., Okano K., Hirayama A., Gotoh A., Li S., Mori T., Katayama T., Ogawa J., Fukuda S., Hase K., Kim Y.G.

Cell Reports (Cell Reports) 40 ( 11 ) 2022.09

Clostridioides difficile causes nosocomial antibiotic-associated diarrhea on a global scale. Susceptibility to C. difficile infection (CDI) is influenced by the composition and metabolism of gut microbiota, which in turn are affected by diet. However, the mechanism underlying the interplay between diet and gut microbiota that modulates susceptibility to CDI remains unclear. Here, we show that a soy protein diet increases the mortality of antibiotic-treated, C. difficile-infected mice while also enhancing the intestinal levels of amino acids (aas) and relative abundance of Lactobacillus genus. Indeed, Ligilactobacillus murinus-mediated fermentation of soy protein results in the generation of aas, thereby promoting C. difficile growth, and the process involves the anchored cell wall proteinase PrtP. Thus, mutual interaction between dietary protein and the gut microbiota is a critical factor affecting host susceptibility to CDI, suggesting that dietary protein sources can be an important determinant in controlling the disease.

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A Novel HDAC1-Selective Inhibitor Attenuates Autoimmune Arthritis by Inhibiting Inflammatory Cytokine Production

Zhe W., Hoshina N., Itoh Y., Tojo T., Suzuki T., Hase K., Takahashi D.

Biological and Pharmaceutical Bulletin (Biological and Pharmaceutical Bulletin) 45 ( 9 ) 1364 - 1372 2022.09

ISSN 09186158

Rheumatoid arthritis (RA) is systemic autoimmune arthritis that causes joint inflammation and destruction. Accumulating evidence has shown that inhibitors of class I histone deacetylases (HDACs) (i.e., HDAC1, 2, 3, and 8) are potential therapeutic candidates as targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs). Nevertheless, the inhibition of class I HDACs has severe adverse effects because of their broad spectrum. We evaluated the therapeutic effect of a novel selective HDAC1 inhibitor TTA03-107 for collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) models in mice. We also examined the effect of TTA03-107 in bone marrow-derived macrophages (BMDMs) and T helper 17 (Th17) cells in vitro. Here, we delineate that TTA03-107 reduced the severity of autoimmune arthritis without obvious adverse effects in CIA and CAIA models. Moreover, TTA03-107 suppressed the production of inflammatory cytokines, such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-17A, in serum and joint tissue. In vitro treatment of BMDMs with TTA03-107 dampened the M1 differentiation and inflammatory cytokine production. TTA03-107 also suppressed the differentiation of Th17 cells. These results demonstrate that TTA03-107 can attenuate the development of arthritis in experimental RA models by inhibiting the differentiation and activation of macrophages and Th17 cells. Therefore, TTA03-107 is a potential tsDMARD candidate.

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<inf>D</inf>-Tryptophan suppresses enteric pathogen and pathobionts and prevents colitis by modulating microbial tryptophan metabolism

Seki N., Kimizuka T., Gondo M., Yamaguchi G., Sugiura Y., Akiyama M., Yakabe K., Uchiyama J., Higashi S., Haneda T., Suematsu M., Hase K., Kim Y.G.

iScience (iScience) 25 ( 8 ) 2022.08

D-Amino acids (D-AAs) have various functions in mammals and microbes. D-AAs are produced by gut microbiota and can act as potent bactericidal molecules. Thus, D-AAs regulate the ecological niche of the intestine; however, the actual impacts of D-AAs in the gut remain unknown. In this study, we show that D-Tryptophan (D-Trp) inhibits the growth of enteric pathogen and colitogenic pathobionts. The growth of Citrobacter rodentium in vitro is strongly inhibited by D-Trp treatment. Moreover, D-Trp protects mice from lethal C. rodentium infection via reduction of the pathogen. Additionally, D-Trp prevents the development of experimental colitis by the depletion of specific microbes in the intestine. D-Trp increases the intracellular level of indole acrylic acid (IA), a key molecule that determines the susceptibility of enteric microbes to D-Trp. Treatment with IA improves the survival of mice infected with C. rodentium. Hence, D-Trp could act as a gut environmental modulator that regulates intestinal homeostasis.

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Cooperative action of gut-microbiota-accessible carbohydrates improves host metabolic function

Tomioka S., Seki N., Sugiura Y., Akiyama M., Uchiyama J., Yamaguchi G., Yakabe K., Ejima R., Hattori K., Kimizuka T., Fujimura Y., Sato H., Gondo M., Ozaki S., Honme Y., Suematsu M., Kimura I., Inohara N., Núñez G., Hase K., Kim Y.G.

Cell Reports (Cell Reports) 40 ( 3 ) 2022.07

Microbiota-accessible carbohydrates (MACs) exert health-promoting effects, but how each MAC impacts gut microbiota and regulates host physiology remains unclear. Here, we show that L-arabinose and sucrose cooperatively act on gut microbiota and exert anti-obesogenic effects. Specifically, L-arabinose, a monosaccharide that is poorly absorbed in the gut and inhibits intestinal sucrase, suppresses diet-induced obesity in mice in the presence of sucrose. Additionally, the suppressive effect of L-arabinose on adiposity is abrogated in mice lacking the short-chain fatty acid (SCFA) receptors GPR43 and GPR41. Mechanistically, L-arabinose increases the relative abundance of acetate and propionate producers (e.g., Bacteroides), while sucrose enhances SCFA production. Furthermore, L-arabinose and sucrose activate the glycolytic and pentose phosphate pathways of Bacteroides, respectively, indicating that they synergistically promote acetate production through distinct pathways. These findings suggest that each MAC has a unique property and thus may serve as a precision gut-microbiota modulator to promote host homeostasis.

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Thymic epithelial cells co-opt lineage-defining transcription factors to eliminate autoreactive T cells

Michelson D.A., Hase K., Kaisho T., Benoist C., Mathis D.

Cell (Cell) 185 ( 14 ) 2542 - 2558.e18 2022.07

Research paper (scientific journal), Joint Work, Accepted, ISSN 00928674

Medullary thymic epithelial cells (mTECs) ectopically express thousands of peripheral-tissue antigens (PTAs), which drive deletion or phenotypic diversion of self-reactive immature T cells during thymic differentiation. Failure of PTA expression causes multiorgan autoimmunity. By assaying chromatin accessibility in individual mTECs, we uncovered signatures of lineage-defining transcription factors (TFs) for skin, lung, liver, and intestinal cells—including Grhl, FoxA, FoxJ1, Hnf4, Sox8, and SpiB—in distinct mTEC subtypes. Transcriptomic and histologic analyses showed that these subtypes, which we collectively term mimetic cells, expressed PTAs in a biologically logical fashion, mirroring extra-thymic cell types while maintaining mTEC identity. Lineage-defining TFs bound to mimetic-cell open chromatin regions and were required for mimetic cell accumulation, whereas the tolerogenic factor Aire was partially and variably required. Expression of a model antigen in mimetic cells sufficed to induce cognate T cell tolerance. Thus, mTECs co-opt lineage-defining TFs to drive mimetic cell accumulation, PTA expression, and self-tolerance.

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Gut microbiota reinforce host antioxidant capacity via the generation of reactive sulfur species

Uchiyama J., Akiyama M., Hase K., Kumagai Y., Kim Y.G.

Cell Reports (Cell Reports) 38 ( 10 ) 2022.03

Gut microbiota act beyond the gastrointestinal tract to regulate the physiology of the host. However, their contribution to the antioxidant capacity of the host remains largely understudied. In this study, we observe that gut bacteria increase the steady-state plasma levels of high-antioxidant molecules, reactive sulfur species (RSS), such as hydrogen sulfide and cysteine persulfide (CysSSH), in the host. Moreover, gut bacteria utilize cystine as a substrate to enzymatically produce CysSSH. Administration of cystine to mice increases their plasma levels of RSS and suppresses the concanavalin-A-induced oxidative stress and liver damage in a gut-microbiota-dependent manner. We find that gut bacteria belonging to the Lachnospiraceae and Ruminococcaceae families have a high capacity to produce RSS, requiring pyridoxal 5′-phosphate for their enzymatic reactions. Collectively, our data demonstrate that gut microbiota enhance the antioxidant capacity of the host through the generation of RSS.

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Skate-skin mucin, rich in sulfated sugars and threonine, promotes proliferation of Akkermansia muciniphila in feeding tests in rats and in vitro fermentation using human feces

Miyata T., Mizushima T., Miyamoto N., Yamada T., Hase K., Fukushima M., Nishimura N., Hino S., Morita T.

Bioscience, Biotechnology and Biochemistry (Bioscience, Biotechnology and Biochemistry) 86 ( 3 ) 397 - 406 2022.03

ISSN 09168451

Dietary factors, affect Akkermansia muciniphila (AM) abundance in the colon, have attracted attention, driven by the inverse correlation between AM abundance and metabolic disorders. We prepared skate-skin mucin (SM), porcine stomach mucin (PM), and rat gastrointestinal mucin (RM). SM contained more sulfated sugars and threonine than PM or RM. Rats were fed a control diet or diets including SM, PM, or RM (15 g/kg), or SM (12 g/kg) from 5 different threonine contents for 14 d. Cecal total bacteria and AM were less and more numerous, respectively, in SM-fed rats than the others, but SM did not affect microbial species richness. Low-Threonine SM did not induce AM proliferation. The in vitro fermentation with human feces showed that the rate of AM increase was greater with SM than PM. Collectively, heavy SM sulfation facilitates a priority supply of SM-derived amino sugars and threonine that promotes AM proliferation in rats and human feces.

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Glia maturation factor-γis involved in S1P-induced marginal zone B-cell chemotaxis and optimal IgM production to type II T-independent antigen

Li Y., Tang Y., Liu J., Meng X., Wang Y., Min Q., Hong R., Tsubata T., Hase K., Wang J.Y.

International Immunology (International Immunology) 34 ( 1 ) 35 - 43 2022.01

ISSN 09538178

Marginal zone B cells (MZBs) represent a unique B-cell sub-population that rapidly differentiate into IgM-secreting plasma cells in response to T-independent (T-I) antigen. Sphingosine 1-phosphate (S1P) promotes MZB localization to the marginal zone. However, intracellular molecules involved in MZB localization and migration remain largely unknown. Here, we show that MZBs lacking the glia maturation factor-γ(GMFG) are impaired in chemotaxis toward S1P under both in vitro and in vivo conditions, suggesting that GMFG is an effector downstream of S1P receptors. GMFG undergoes serine phosphorylation upon S1P stimulation and is required for S1P-induced desensitization of S1P receptor 1 (S1PR1). Compared with wild-type mice, Gmfg-/- mice produce elevated levels of 4-hydroxy-3-nitrophenyl-acetyl (NP)-specific IgM against a T-I type II antigen, NP-Ficoll, accompanied by dysregulated MZB localization. These results identify GMFG as a regulator of S1P-induced MZB chemotaxis and reveal a role for MZB localization in the marginal zone for optimal IgM production against a T-I antigen.

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