記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

Introduction

Campylobacter spp. are a public health concern, yet there is still no effective vaccine or medicine available.

Methods

Here, we developed a Campylobacter jejuni-specific antibody and found that it targeted a menaquinol cytochrome c reductase complex QcrC.

Results

The antibody was specifically reactive to multiple C. jejuni strains including clinical isolates from patients with acute enteritis and was found to inhibit the energy metabolism and growth of C. jejuni. Different culture conditions produced different expression levels of QcrC in C. jejuni, and these levels were closely related not only to the energy metabolism of C. jejuni but also its pathogenicity. Furthermore, immunization of mice with recombinant QcrC induced protective immunity against C. jejuni infection.

Discussion

Taken together, our present findings highlight a possible antibody- or vaccination-based strategy to prevent or control Campylobacter infection by targeting the QcrC-mediated metabolic pathway.

DOI： 10.3389/fmicb.2024.1415893

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

Intestinal bacteria metabolize dietary substances to produce bioactive postbiotics, among which some are recognized for their role in promoting host health. We here explored the postbiotic potential of two omega-3 α-linolenic acid–derived metabolites: trans-10-cis-15-octadecadienoic acid (t10,c15-18:2) and cis-9-cis-15-octadecadienoic acid (c9,c15-18:2). Dietary intake of lipids rich in omega-3 α-linolenic acid elevated levels of t10,c15-18:2 and c9,c15-18:2 in the serum and feces of mice, an effect dependent on the presence of intestinal bacteria. Notably, t10,c15-18:2 mitigated skin inflammation in mice that became hypersensitive after exposure to 2,4-dinitrofluorobenzene, an experimental model for allergic contact dermatitis. In particular, t10,c15-18:2—but not c9,c15-18:2—attenuated ear swelling and edema, characteristic symptoms of contact hypersensitivity. The anti-inflammatory effects of t10,c15-18:2 were due to its ability to suppress the release of vascular endothelial growth factor A from keratinocytes, thereby mitigating the enhanced vascular permeability induced by hapten stimulation. Our study identified retinoid X receptor as a functional receptor that mediates the downregulation of skin inflammation upon treatment with t10,c15-18:2. Our results suggest that t10,c15-18:2 holds promise as an omega-3 fatty acid–derived postbiotic with potential therapeutic implications for alleviating the skin edema seen in allergic contact dermatitis–induced inflammation.

DOI： 10.3389/fcimb.2024.1355679

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DOI： 10.1021/jacs.3c12581

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

Abstract

We previously demonstrated that Alcaligenes-derived lipid A (ALA), which is produced from an intestinal lymphoid tissue-resident commensal bacterium, is an effective adjuvant for inducing antigen-specific immune responses. To understand the immunologic characteristics of ALA as a vaccine adjuvant, we here compared the adjuvant activity of ALA with that of a licensed adjuvant (monophosphoryl lipid A, MPLA) in mice. Although the adjuvant activity of ALA was only slightly greater than that of MPLA for subcutaneous immunization, ALA induced significantly greater IgA antibody production than did MPLA during nasal immunization. Regarding the underlying mechanism, ALA increased and activated CD11b+ CD103− CD11c+ dendritic cells in the nasal tissue by stimulating chemokine responses. These findings revealed the superiority of ALA as a mucosal adjuvant due to the unique immunologic functions of ALA in nasal tissue.

DOI： 10.1093/intimm/dxad045

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Immune cell activation is essential for cancer rejection; however, the tumor microenvironment leads to deterioration of immune function, which enables cancer cells to survive and proliferate. We previously reported that oral ingestion of Lentinula Edodes Mycelia (L.E.M.) extract enhances the tumor antigen-specific T-cell response and exerts an antitumor effect in a tumor-bearing mouse model. In this study, we focused on antigen-presenting cells (APCs) located upstream of the immune system, induced a T-cell response, then examined the impact of L.E.M. extract on the APCs. L.E.M. extract enhanced the expression of MHC-I, MHC-II, CD86, CD80, and CD40 in bone marrow-derived dendritic cells (DCs) and strongly induced the production of IL-12. L.E.M.-stimulated DCs enhanced IFN-γ production from CD8⁺ T cells and induced their differentiation into effector cells. Furthermore, L.E.M. extract promoted IL-12 production and suppressed the production of IL-10 and TGF-β by transforming bone marrow-derived macrophages into M1-like macrophages. Furthermore, in a B16F10 melanoma inoculation model, DCs in the spleen were decreased and their activation was suppressed by the presence of cancer; however, ingestion of L.E.M. extract prevented this functional deterioration of DCs. In the spleen of cancer-bearing mice, the number of CD11b⁻ F4/80⁺ macrophages in a hypoactivated state was also increased, whereas L.E.M. extract suppressed the increase of such macrophages. These findings suggest that L.E.M. extract may exhibit an antitumor immune response by regulating the function of APCs to induce cytotoxic T lymphocytes, as well as by suppressing the decline in antigen-presenting cell activity caused by the presence of cancer.

DOI： 10.1186/s12906-023-04106-5

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その他リンク： https://link.springer.com/article/10.1186/s12906-023-04106-5/fulltext.html

掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

Macrophages manifest as various subtypes that play diverse and important roles in immunosurveillance and the maintenance of immunological homeostasis in various tissues. Many in vitro studies divide macrophages into two broad groups: M1 macrophages induced by lipopolysaccharide (LPS), and M2 macrophages induced by interleukin 4 (IL-4). However, considering the complex and diverse microenvironment in vivo, the concept of M1 and M2 is not enough to explain diversity of macrophages. In this study, we analyzed the functions of macrophages induced by simultaneous stimulation with LPS and IL-4 (termed LPS/IL-4-induced macrophages). LPS/IL-4-induced macrophages were a homogeneous population showing a mixture of the characteristics of M1 and M2 macrophages. In LPS/IL-4-induced macrophages, expression of cell-surface M1 markers (I-A^b) was higher than in M1 macrophages, but lower expression of iNOS, and expression of M1-associated genes (Tnfα and Il12p40) were decreased in comparison to expression in M1 macrophages. Conversely, expression of the cell-surface M2 marker CD206 was lower on LPS/IL-4-induced macrophages than on M2 macrophages and expression of M2-associated genes (Arg1, Chi3l3, and Fizz1) varied, with Arg1 being greater than, Fizz1 being lower than, and Chi3l3 being comparable to that in M2 macrophages. Glycolysis-dependent phagocytic activity of LPS/IL-4-induced macrophages was strongly enhanced as was that of M1 macrophages; however, the energy metabolism of LPS/IL-4-induced macrophages, such as activation state of glycolytic and oxidative phosphorylation, was quite different from that of M1 or M2 macrophages. These results indicate that the macrophages induced by LPS and IL-4 had unique properties.

DOI： 10.3389/fimmu.2023.1111729

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

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.

DOI： 10.1038/s41598-023-32552-1

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その他リンク： https://www.nature.com/articles/s41598-023-32552-1

掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.intimp.2023.109852

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3389/fmolb.2023.1097955

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.jnutbio.2022.109219

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

The gut microbiome is an important determinant in various diseases. Here we perform a cross-sectional study of Japanese adults and identify the Blautia genus, especially B. wexlerae, as a commensal bacterium that is inversely correlated with obesity and type 2 diabetes mellitus. Oral administration of B. wexlerae to mice induce metabolic changes and anti-inflammatory effects that decrease both high-fat diet–induced obesity and diabetes. The beneficial effects of B. wexlerae are correlated with unique amino-acid metabolism to produce S-adenosylmethionine, acetylcholine, and l-ornithine and carbohydrate metabolism resulting in the accumulation of amylopectin and production of succinate, lactate, and acetate, with simultaneous modification of the gut bacterial composition. These findings reveal unique regulatory pathways of host and microbial metabolism that may provide novel strategies in preventive and therapeutic approaches for metabolic disorders.

DOI： 10.1038/s41467-022-32015-7

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その他リンク： https://www.nature.com/articles/s41467-022-32015-7

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Dietary ω3 fatty acids have important health benefits and exert their potent bioactivity through conversion to lipid mediators. Here, we demonstrate that microbiota play an essential role in the body's use of dietary lipids for the control of inflammatory diseases. We found that amounts of 10-hydroxy-cis-12-cis-15-octadecadienoic acid (αHYA) and 10-oxo-cis-12-cis-15-octadecadienoic acid (αKetoA) increased in the feces and serum of specific-pathogen-free, but not germ-free, mice when they were maintained on a linseed oil diet, which is high in α-linolenic acid. Intake of αKetoA, but not αHYA, exerted anti-inflammatory properties through a peroxisome proliferator-activated receptor (PPAR)γ-dependent pathway and ameliorated hapten-induced contact hypersensitivity by inhibiting the development of inducible skin-associated lymphoid tissue through suppression of chemokine secretion from macrophages and inhibition of NF-κB activation in mice and cynomolgus macaques. Administering αKetoA also improved diabetic glucose intolerance by inhibiting adipose tissue inflammation and fibrosis through decreased macrophage infiltration in adipose tissues and altering macrophage M1/M2 polarization in mice fed a high-fat diet. These results collectively indicate that αKetoA is a novel postbiotic derived from α-linolenic acid, which controls macrophage-associated inflammatory diseases and may have potential for developing therapeutic drugs as well as probiotic food products.

DOI： 10.1038/s41385-021-00477-5

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

We previously identified Alcaligenes spp. as a commensal bacterium that resides in lymphoid tissues, including Peyer’s patches. We found that Alcaligenes-derived lipopolysaccharide acted as a weak agonist of Toll-like receptor four due to the unique structure of lipid A, which lies in the core of lipopolysaccharide. This feature allowed the use of chemically synthesized Alcaligenes lipid A as a safe synthetic vaccine adjuvant that induces Th17 polarization to enhance systemic IgG and respiratory IgA responses to T-cell–dependent antigens (e.g., ovalbumin and pneumococcal surface protein A) without excessive inflammation. Here, we examined the adjuvant activity of Alcaligenes lipid A on a Haemophilus influenzae B conjugate vaccine that contains capsular polysaccharide polyribosyl ribitol phosphate (PRP), a T-cell–independent antigen, conjugated with the T-cell–dependent tetanus toxoid (TT) antigen (i.e., PRP-TT). When mice were subcutaneously immunized with PRP alone or mixed with TT, Alcaligenes lipid A did not affect PRP-specific IgG production. In contrast, PRP-specific serum IgG responses were enhanced when mice were immunized with PRP-TT, but these responses were impaired in similarly immunized T-cell—deficient nude mice. Furthermore, TT-specific—but not PRP-specific—T-cell activation occurred in mice immunized with PRP-TT together with Alcaligenes lipid A. In addition, coculture with Alcaligenes lipid A promoted significant proliferation of and enhanced antibody production by B cells. Together, these findings suggest that Alcaligenes lipid A exerts an adjuvant activity on thymus-independent Hib polysaccharide antigen in the presence of a T-cell–dependent conjugate carrier antigen.

DOI： 10.3389/fphar.2021.763657

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

Alcaligenes spp., including A. faecalis, is a gram-negative facultative bacterium uniquely residing inside the Peyer’s patches. We previously showed that A. faecalis-derived lipopolysaccharides (Alcaligenes LPS) acts as a weak agonist of toll-like receptor 4 to activate dendritic cells and shows adjuvant activity by enhancing IgG and Th17 responses to systemic vaccination. Here, we examined the efficacy of Alcaligenes LPS as a nasal vaccine adjuvant. Nasal immunization with ovalbumin (OVA) plus Alcaligenes LPS induced follicular T helper cells and germinal center formation in the nasopharynx-associated lymphoid tissue (NALT) and cervical lymph nodes (CLNs), and consequently enhanced OVA-specific IgA and IgG responses in the respiratory tract and serum. In addition, nasal immunization with OVA plus Alcaligenes LPS induced OVA-specific T cells producing IL-17 and/or IL-10, whereas nasal immunization with OVA plus cholera toxin (CT) induced OVA-specific T cells producing IFN-γ and IL-17, which are recognized as pathogenic type of Th17 cells. In addition, CT, but not Alcaligenes LPS, promoted the production of TNF-α and IL-5 by T cells. Nasal immunization with OVA plus CT, but not Alcaligenes LPS, led to increased numbers of neutrophils and eosinophils in the nasal cavity. Together, these findings indicate that the benign nature of Alcaligenes LPS is an effective nasal vaccine adjuvant that induces antigen-specific mucosal and systemic immune responses without activation of inflammatory cascade after nasal administration.

DOI： 10.3389/fimmu.2021.699349

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Atherosclerosis is a chronic inflammatory disease associated with macrophage aggregate and transformation into foam cells. In this study, we sought to investigate the impact of dietary intake of ω3 fatty acid on the development of atherosclerosis, and demonstrate the mechanism of action by identifying anti-inflammatory lipid metabolite. Mice were exposed to a high-fat diet (HFD) supplemented with either conventional soybean oil or α-linolenic acid-rich linseed oil. We found that as mice became obese they also showed increased pulsatility and resistive indexes in the common carotid artery. In sharp contrast, the addition of linseed oil to the HFD improved pulsatility and resistive indexes without affecting weight gain. Histological analysis revealed that dietary linseed oil inhibited foam cell formation in the aortic valve. Lipidomic analysis demonstrated a particularly marked increase in the eicosapentaenoic acid-derived metabolite 12-hydroxyeicosapentaenoic acid (12-HEPE) in the serum from mice fed with linseed oil. When we gave 12-HEPE to mice with HFD, the pulsatility and resistive indexes was improved. Indeed, 12-HEPE inhibited the foamy transformation of macrophages in a peroxisome proliferator-activated receptor (PPAR)γ-dependent manner. These results demonstrate that the 12-HEPE-PPARγ axis ameliorates the pathogenesis of atherosclerosis by inhibiting foam cell formation.

DOI： 10.1038/s41598-021-89707-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We analyzed the mechanisms underlying enhanced IgA production in the cells of Peyer's patch cells via membrane vesicles derived from Lactobacillus sakei subsp. sakei NBRC 15893. Depletion of CD11c+ cells from Peyer's patch cells suppressed the enhanced IgA production mediated by membrane vesicles. Meanwhile, stimulation of bone marrow-derived dendritic cells with membrane vesicles increased gene expression of inducible nitric oxide synthase, retinaldehyde dehydrogenase 2, and several inflammatory cytokines. The production of nitric oxide and interleukin (IL)-6 by membrane vesicle stimulation was induced via Toll-like receptor 2 on bone marrow-derived dendritic cells. Inhibition of inducible nitric oxide synthase and retinaldehyde dehydrogenase 2, as well as neutralization of IL-6 in Peyer's patch cells, suppressed the enhanced IgA production by membrane vesicle stimulation. Hence, nitric oxide, retinoic acid, and IL-6 induced by MVs play crucial roles in the enhanced IgA production elicited by membrane vesicles in Peyer's patch cells.

DOI： 10.1093/bbb/zbab065

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1096/fj.202001687r

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1096/fj.202001687R

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

T-cell development depends on the thymic microenvironment, in which endothelial cells (ECs) play a vital role. Interestingly, vascular permeability of the thymic cortex is lower than in other organs, suggesting the existence of a blood-thymus barrier (BTB). On the other hand, blood-borne molecules and dendritic cells bearing self-antigens are accessible to the medulla, facilitating central tolerance induction, and continuous T-precursor immigration and mature thymocytes egress occur through the vessels at cortico-medullary junctions (CMJ). We found that claudin-5 (Cld5), a membrane protein of tight junctions, was expressed in essentially all ECs of the cortical vasculatures, whereas approximately half of the ECs of the medulla and CMJ lacked Cld5 expression. An intravenously (iv)-injected biotin tracer hardly penetrated cortical Cld5 + vessels, but it leaked into the medullary parenchyma through Cld5 - vessels. Cld5 expression in an EC cell line caused a remarkable increase in trans-endothelial resistance in vitro, and the biotin tracer leaked from the cortical vasculatures in Cldn5-/- mice. Furthermore, iv-injected sphingosine-1 phosphate distributed selectively into the medulla through the Cld5 - vessels, probably ensuring the egress of CD3 high mature thymocytes from Cld5 - vessels at the CMJ. These results suggest that distinct Cld5 expression profiles in the cortex and medulla may control the BTB and T-cell gateway to blood circulation, respectively.

DOI： 10.1093/intimm/dxaa069

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Lymphoid-tissue-resident commensal bacteria (LRCs), including Alcaligenes faecalis, are present in intestinal lymphoid tissue including the Peyer's patches (PPs) of mammals and modulate the host immune system. Although LRCs can colonize within dendritic cells (DCs), the mechanisms through which LRCs persist in DCs and the symbiotic relationships between LRCs and DCs remain to be investigated. Here, we show an intracellular symbiotic system in which the LRC Alcaligenes creates a unique energy shift in DCs. Whereas DCs showed low mitochondrial respiration when they were co-cultured with Escherichia coli, DCs carrying A. faecalis maintained increased mitochondrial respiration. Furthermore, E. coli induced apoptosis of DCs but A. faecalis did not. Regarding an underlying mechanism, A. faecalis-unlike E. coli-did not induce intracellular nitric oxide (NO) production in DCs due to the low activity of its lipopolysaccharide (LPS). Therefore, A. faecalis, an example of LRCs, may persist within intestinal lymphoid tissue because they elicit little NO production in DCs. In addition, the symbiotic DCs exhibit characteristic physiologic changes, including a low rate of apoptosis and increased mitochondrial respiration.

DOI： 10.3389/fmicb.2020.561005

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Homeostatic generation of T cells, which occurs in the thymus, is controlled at least in part by endogenous cytokines and ligands. In addition, nutritional factors are other key regulators for the homeostasis of host immunity, but whether and how nutrition affects the homeostatic generation of thymocytes remains to be established. Here, we showed that vitamin B1 deficiency resulted in a bias toward the maturation of γδ thymocytes accompanied by decreased differentiation into double-positive thymocytes during thymic involution. These events were mediated through the increased production of TGF-β superfamily members due to the accumulation of branched-chain α-keto acids in thymic stromal cells. These findings revealed essential roles of vitamin B1 in the appropriate differentiation of T cells through the metabolism of thymic stromal cells.

DOI： 10.1016/j.isci.2020.101426

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Effective and safe vaccine adjuvants are needed to appropriately augment mucosal vaccine effects. Our previous study demonstrated that lipopolysaccharide (LPS) from Peyer's patch resident Alcaligenes stimulated dendritic cells to promote the production of mucosal immunity-enhancing cytokines (e.g., IL-6 and BAFF), thus enhancing antigen-specific immune responses (including IgA production and Th17 responses) without excessive inflammation. Here, we chemically synthesized Alcaligenes lipid A, the biologically active part of LPS, and examined its efficacy as a nasal vaccine adjuvant for the induction of protectively immunity against Streptococcus pneumoniae infection. Mice were nasally immunized with pneumococcal surface protein A (PspA) as a vaccine antigen for S. pneumoniae, together with Alcaligenes lipid A. Alcaligenes lipid A supported the generation of high levels of PspA-specific IgA and IgG responses through the augmentation of germinal center formation in the nasopharynx-associated lymphoid tissue and cervical lymph nodes (CLNs). Moreover, Alcaligenes lipid A promoted PspA-specific CD4+ Th17 responses in the CLNs and spleen. Furthermore, neutrophils were recruited to infection sites upon nasal infection and synchronized with the antigen-specific T and B cell responses, resulting in the protection against S. pneumoniae infection. Taken together, Alcaligenes lipid A could be applied to the prospective adjuvant to enhance nasal vaccine efficacy by means of augmenting both the innate and acquired arms of mucosal immunity against respiratory bacterial infection.

DOI： 10.3390/microorganisms8081102

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Alcaligenes spp. are identified as commensal bacteria and have been found to inhabit Peyer's patches in the gut. We previously reported that Alcaligenes-derived lipopolysaccharides (LPS) exerted adjuvant activity in systemic vaccination, without excessive inflammation. Lipid A is one of the components responsible for the biological effect of LPS and has previously been applied as an adjuvant. Here, we examined the adjuvant activity and safety of chemically synthesized Alcaligenes lipid A. We found that levels of OVA-specific serum IgG antibodies increased in mice that were subcutaneously immunized with ovalbumin (OVA) plus Alcaligenes lipid A relative to those that were immunized with OVA alone. In addition, Alcaligenes lipid A promoted antigen-specific T helper 17 (Th17) responses in the spleen; upregulated the expression of MHC class II, CD40, CD80, and CD86 on bone marrow-derived dendritic cells (BMDCs); enhanced the production of Th17-inducing cytokines IL-6 and IL-23 from BMDCs. Stimulation with Alcaligenes lipid A also induced the production of IL-6 and IL-1β in human peripheral blood mononuclear cells. Moreover, Alcaligenes lipid A caused minor side effects, such as lymphopenia and thrombocytopenia. These findings suggest that Alcaligenes lipid A is a safe and effective Th17-type adjuvant by directly stimulating dendritic cells in systemic vaccination.

DOI： 10.3390/vaccines8030395

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Nasal mucosal tissues are equipped with physical barriers, mucus and cilia, on their surface. The mucus layer captures inhaled materials, and the cilia remove the inhaled materials from the epithelial layer by asymmetrical beating. The effect of nasal physical barriers on the vaccine efficacy remains to be investigated. Tubulin tyrosine ligase-like family member 1 (Ttll1) is an essential enzyme for appropriate movement of the cilia on respiratory epithelium, and its deficiency (Ttll1-KO) leads to mucus accumulation in the nasal cavity. Here, when mice were intranasally immunized with pneumococcal surface protein A (PspA, as vaccine antigen) together with cholera toxin (CT, as mucosal adjuvant), Ttll1-KO mice showed higher levels of PspA-specific IgA in the nasal wash and increased numbers of PspA-specific IgA-producing plasma cells in the nasal passages when compared with Ttll1 hetero (He) mice. Mucus removal by N-acetylcysteine did not affect the enhanced immune responses in Ttll1-KO mice versus Ttll1-He mice. Immunohistological and flow cytometry analyses revealed that retention time of PspA in the nasal cavity in Ttll1-KO mice was longer than that in Ttll1-He mice. Consistently, uptake of PspA by dendritic cells was higher in the nasopharynx-associated lymphoid tissue (NALT) of Ttll1-KO mice than that of Ttll1-He mice. These results indicate that the ciliary function of removing vaccine antigen from the NALT epithelial layer is a critical determinant of the efficacy of nasal vaccine.

DOI： 10.1093/intimm/dxaa029

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Accumulating evidence has revealed that lymphoid tissue-resident commensal bacteria (e.g. Alcaligenes spp.) survive within dendritic cells. We extended our previous study by investigating microbes that persistently colonize colonic macrophages. 16S rRNA-based metagenome analysis using DNA purified from murine colonic macrophages revealed the presence of Stenotrophomonas maltophilia. The in situ intracellular colonization by S. maltophilia was recapitulated in vitro by using bone marrow-derived macrophages (BMDMs). Co-culture of BMDMs with clinically isolated S. maltophilia led to increased mitochondrial respiration and robust IL-10 production. We further identified a 25-kDa protein encoded by the gene assigned as smlt2713 (recently renamed as SMLT_RS12935) and secreted by S. maltophilia as the factor responsible for enhanced IL-10 production by BMDMs. IL-10 production is critical for maintenance of the symbiotic condition, because intracellular colonization by S. maltophilia was impaired in IL-10-deficient BMDMs, and smlt2713-deficient S. maltophilia failed to persistently colonize IL-10-competent BMDMs. These findings indicate a novel commensal network between colonic macrophages and S. maltophilia that is mediated by IL-10 and smlt2713.

DOI： 10.1093/intimm/dxz071

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Maternal dietary exposures are considered to influence the development of infant allergies through changes in the composition of breast milk. Cohort studies have shown that ω3 PUFA in breast milk may have a beneficial effect on the preventing of allergies in infants; however, the underlying mechanisms remain to be investigated. We investigated how the maternal intake of dietary ω3 PUFAs affects fatty acid profiles in the breast milk and their pups and reduced the incidence of allergic diseases in the pups. METHODS: Contact hypersensitivity (CHS) induced by 2,4-dinitrofluorobenzene and fluorescein isothiocyanate was applied to the skin in pups reared by mother maintained with diets mainly containing ω3 or ω6 PUFAs. Skin inflammation, immune cell populations and expression levels of immunomodulatory molecules in pups and/or human cell line were investigated by using flow cytometric, immunohistologic, and quantitative RT-PCR analyses. ω3 PUFA metabolites in breast milk and infant's serum were evaluated by lipidomics analysis using LC-MS/MS. RESULTS: We show that maternal intake of linseed oil, containing abundant ω 3 α-linolenic acid, resulted in the increased levels of ω 3 docosapentaenoic acid (DPA) and its 14-lipoxygenation products in the breast milk of mouse dams; these metabolites increased the expression of TNF-related apoptosis-inducing ligand (TRAIL) on plasmacytoid dendritic cells (pDCs) in their pups and thus inhibited infant CHS. Indeed, the administration of DPA-derived 14-lipoxygenation products to mouse pups ameliorated their DNFB CHS. CONCLUSION: These findings suggest that an inhibitory mechanism in infant skin allergy is induced through maternal metabolism of dietary ω3 PUFAs in mice.

DOI： 10.1111/all.14217

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記述言語：英語  

DOI： 10.1002/2211-5463.12735

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Dietary intake of ω3 polyunsaturated fatty acids such as eicosapentaenoic acid and docosahexaenoic acid is beneficial for health control. We recently identified 17,18-epoxyeicosatetraenoic acid (17,18-EpETE) as a lipid metabolite endogenously generated from eicosapentaenoic acid that exhibits potent anti-allergic and anti-inflammatory properties. However, chemically synthesized 17,18-EpETE is enantiomeric due to its epoxy group-17(S),18(R)-EpETE and 17(R),18(S)-EpETE. In this study, we demonstrated stereoselective differences of 17(S),18(R)-EpETE and 17(R),18(S)-EpETE in amelioration of skin contact hypersensitivity and found that anti-inflammatory activity was detected in 17(S),18(R)-EpETE, but not in 17(R),18(S)-EpETE. In addition, we found that cytochrome P450 BM-3 derived from Bacillus megaterium stereoselectively converts EPA into 17(S),18(R)-EpETE, which effectively inhibited the development of skin contact hypersensitivity by inhibiting neutrophil migration in a G protein-coupled receptor 40-dependent manner. These results suggest the new availability of a bacterial enzyme to produce a beneficial lipid mediator, 17(S),18(R)-EpETE, in a stereoselective manner. Our findings highlight that bacterial enzymatic conversion of fatty acid is a promising strategy for mass production of bioactive lipid metabolites.

DOI： 10.1096/fba.2019-00061

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掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/nu11122868

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41385-019-0175-z

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担当区分：筆頭著者  

DOI： 10.1093/intimm/dxy086

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/all.13762

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3389/fnut.2019.00036

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/intimm/dxy071

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Nature Publishing Group  

DOI： 10.1038/s41598-018-21120-7

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

We previously reported that Ag85B-expressing human parainfluenza type 2 virus (Ag85B-rHPIV2) was effective as a nasal vaccine against tuberculosis in mice; however, the mechanism by which it induces an immune response remains to be investigated. In the present study, we found that organogenesis of inducible bronchus-associated lymphoid tissue (iBALT) played a role in the induction of antigen-specific T cells and IgA antibody responses in the lung of mice intra-nasally administered Ag85B-rHPIV2. We found that expression of Ag85B was dispensable for the development of iBALT, suggesting that HPIV2 acted as an iBALT-inducing vector. When iBALT organogenesis was disrupted in Ag85B-rHPIV2-immunized mice, either by neutralization of the lymphotoxin pathway or depletion of CD11b+ cells, Ag85B-specific immune responses (i.e. IFN γ-producing T cells and IgA antibody) were diminished in the lung. Furthermore, we found that immunization with Ag85B-rHPIV2 induced neutrophil and eosinophil infiltration temporally after the immunization in the lung. Thus, our results show that iBALT organogenesis contributes to the induction of antigen-specific immune responses by Ag85B-rHPIV2 and that Ag85B-rHPIV2 provokes its immune responses without inducing long-lasting inflammation.

DOI： 10.1093/intimm/dxy046

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Metabolites of eicosapentaenoic acid exert various physiologic actions. 17,18-Epoxyeicosatetraenoic acid (17,18-EpETE) is a recently identified new class of antiallergic and anti-inflammatory lipid metabolite of eicosapentaenoic acid, but its effects on skin inflammation and the underlying mechanisms remain to be investigated. OBJECTIVE: We evaluated the effectiveness of 17,18-EpETE for control of contact hypersensitivity in mice and cynomolgus macaques. We further sought to reveal underlying mechanisms by identifying the responsible receptor and cellular target of 17,18-EpETE. METHODS: Contact hypersensitivity was induced by topical application of 2,4-dinitrofluorobenzene. Skin inflammation and immune cell populations were analyzed by using flow cytometric, immunohistologic, and quantitative RT-PCR analyses. Neutrophil mobility was examined by means of imaging analysis in vivo and neutrophil culture in vitro. The receptor for 17,18-EpETE was identified by using the TGF-α shedding assay, and the receptor's involvement in the anti-inflammatory effects of 17,18-EpETE was examined by using KO mice and specific inhibitor treatment. RESULTS: We found that preventive or therapeutic treatment with 17,18-EpETE ameliorated contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques. 17,18-EpETE was recognized by G protein-coupled receptor (GPR) 40 (also known as free fatty acid receptor 1) and inhibited chemoattractant-induced Rac activation and pseudopod formation in neutrophils. Indeed, the antiallergic inflammatory effect of 17,18-EpETE was abolished in the absence or inhibition of GPR40. CONCLUSION: 17,18-EpETE inhibits neutrophil mobility through GPR40 activation, which is a potential therapeutic target to control allergic inflammatory diseases.

DOI： 10.1016/j.jaci.2017.09.053

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.celrep.2018.03.104

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-017-14292-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Metagenomic analysis based on the 16S rRNA gene is generally performed to examine the diversity and abundance of commensal bacteria in feces, which is now recognized to be associated with human health and diseases. Guanidine thiocyanate (GuSCN) solution is used as a less onerous way compared with a frozen method to transport and stock fecal samples at room temperature for DNA analysis; however, optimal methods to measure fecal bacterial composition in GuSCN solution remain to be investigated. Here, we examined the influence of various factors such as pretreatment (e.g., removing GuSCN solution and washing feces with phosphate-buffered saline (PBS) before mechanical lysis), fecal concentration in the GuSCN solution, storage time, and position of fecal subsampling on the 16S rRNA-based analysis of fecal bacteria in GuSCN solution. We found that pretreatment and fecal concentration affected the bacterial composition, and a little change was noted with subsampling position. Based on these results, we propose a basic protocol, including fecal sampling, sample storage, and DNA extraction, for the 16S rRNA-based analysis of bacterial composition in feces suspended in GuSCN solution.

DOI： 10.1038/s41598-017-04511-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.immuni.2016.11.010

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.celrep.2015.08.063

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/imm.12445

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/srep09750

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0127460

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0090638

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担当区分：筆頭著者  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1398-9995.2011.02782.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.chom.2011.04.010

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.4049/jimmunol.0903794

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1084/jem.20091436

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.vaccine.2006.10.014

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：日本語  

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開催年月日： 2021年6月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

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開催年月日： 2021年6月

記述言語：英語   会議種別：口頭発表（招待・特別）  

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開催年月日： 2021年1月

記述言語：英語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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開催年月日： 2020年12月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

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開催年月日： 2020年9月

記述言語：日本語   会議種別：口頭発表（一般）  

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開催年月日： 2020年1月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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開催年月日： 2019年7月

記述言語：英語   会議種別：口頭発表（一般）  

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開催年月日： 2019年6月

記述言語：英語   会議種別：ポスター発表  

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開催年月日： 2019年3月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

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開催年月日： 2019年1月

記述言語：日本語   会議種別：口頭発表（一般）  

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開催年月日： 2018年12月

記述言語：英語   会議種別：口頭発表（一般）  

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開催年月日： 2018年12月

記述言語：日本語   会議種別：口頭発表（一般）  

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開催年月日： 2018年5月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

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開催年月日： 2018年1月

記述言語：英語   会議種別：ポスター発表  

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開催年月日： 2017年12月

記述言語：英語   会議種別：口頭発表（一般）  

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開催年月日： 2016年12月

記述言語：英語   会議種別：ポスター発表  

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開催年月日： 2016年10月

記述言語：日本語   会議種別：口頭発表（一般）  

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開催年月日： 2016年8月

記述言語：英語   会議種別：口頭発表（一般）  

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開催年月日： 2016年6月

記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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開催年月日： 2016年5月

記述言語：英語   会議種別：ポスター発表  

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開催年月日： 2016年1月

記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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開催年月日： 2015年11月

記述言語：英語   会議種別：口頭発表（一般）  

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開催年月日： 2015年5月

記述言語：日本語   会議種別：口頭発表（一般）  

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開催年月日： 2014年6月

記述言語：日本語   会議種別：ポスター発表  

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開催年月日： 2013年12月

記述言語：英語   会議種別：口頭発表（一般）  

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開催年月日： 2012年12月

記述言語：英語   会議種別：口頭発表（一般）  

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開催年月日： 2012年11月

記述言語：英語   会議種別：口頭発表（一般）  

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開催年月日： 2010年1月

記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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開催年月日： 2009年12月

記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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開催年月日： 2008年12月

記述言語：英語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：口頭発表（招待・特別）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：ポスター発表  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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研究所近隣の小学生や中学生を中心に、全体の参加者は1000名を越える地域に根ざした毎年恒例のイベントである。当研究室では、1回のイベント30分30名程を対象に1日5回のスケジュールで参加型イベントを行っている。
2018年は、比重や表面張力に関する実験を行った。コーヒーに牛乳を入れると分離するが、かき混ぜると混ざる。一方、水に油を入れると分離するが、かき混ぜても分離したままである。この違いは何か？について１円玉を様々な液体に浮かべる実験を行って理解した。最後に、色を付けた水と油を使って、オリジナルの飾り瓶を作ってプレゼントした。この飾り瓶はかき混ぜても、、、である。

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研究所近隣の小学生や中学生を中心に、全体の参加者は1000名を越える地域に根ざした毎年恒例のイベントである。当研究室では、1回のイベント30分30名程を対象に1日5回のスケジュールで参加型イベントを行っている。
2017年は、光の屈折を体験する実験を行った。紙芝居の主人公が3つの課題に挑戦！参加者に実験を行ってもらい課題の答えを導き出して物語のゴールへ。プラスチックコップ、水、園芸用保水剤、コイン、ヤスリ、セロハンテープなど身近なものを使って、3つの異なった実験により異なった観点で光の屈折を体験できる内容とした。（１）園芸用保水剤が入ったコップの背面には何が書かれている？水を入れるだけ！（２）コップの底に置かれたコインの色は？覗かないでもわかる。（３）プラスチックコップに細かい傷がついてコップの背面の文字が読めない。どうしたら読める？

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研究所近隣の小学生や中学生を中心に、全体の参加者は1000名を越える地域に根ざした毎年恒例のイベントである。当研究室では、1回のイベント30分30名程を対象に1日5回のスケジュールで参加型イベントを行っている。
2016年は、うがい薬の色の変化を見ることで食品中のビタミンCの濃度を測定した。オレンジ、グレープフルーツ、レモンの果汁（搾り汁）と緑茶を用意し、ビタミンC含有量の順位予想をしたのち、参加者が実際に測定（滴定）を行い結果を判定した。一般的にレモンがビタミンCの代表格として認知度が高いが、この中でもっともビタミンC含有量が高かったのは、、、である。

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研究所近隣の小学生や中学生を中心に、全体の参加者は1000名を越える地域に根ざした毎年恒例のイベントである。当研究室では、1回のイベント30分30名程を対象に1日5回のスケジュールで参加型イベントを行っている。
2015年は、アルギン酸ナトリウムを使って人工イクラを作製した。食紅で色をつけ赤とオレンジの本物のイクラのような色合いを出した。また、紫や青、緑などオリジナルカラーの人工イクラも作製した。私が作製した人工イクラの色は、「紫紺」である。

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研究所近隣の小学生や中学生を中心に、全体の参加者は1000名を越える地域に根ざした毎年恒例のイベントである。当研究室では、1回のイベント30分30名程を対象に1日5回のスケジュールで参加型イベントを行っている。
2014年は、比重の違いを利用して物質を分ける実験を行った。濃度の異なった食塩水を3種類用意し、それぞれを食紅により色分けした。これらを重層して3層に分離した食塩溶液を作製した。この食塩溶液に種類の異なる野菜を切ったもの（例：さつまいも、大根、人参）を投入し、どの層の位置で静止するかを調べることで、それぞれの野菜に固有の比重があることを学んだ。また、野菜を１つ選び、大中小大きさを変えて切り、大きさが違うと静止する位置がどうなるかクイズ形式で行った。正解は、、、である。

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研究所近隣の小学生や中学生を中心に、全体の参加者は1000名を越える地域に根ざした毎年恒例のイベントである。当研究室では、1回のイベント30分30名程を対象に1日5回のスケジュールで参加型イベントを行っている。
2013年は、うがい薬の色の変化を見ることで食品中のビタミンCの濃度を測定した。オレンジ、グレープフルーツ、レモンの果汁（搾り汁）と緑茶を用意し、ビタミンC含有量の順位予想をしたのち、参加者が実際に測定（滴定）を行い結果を判定した。一般的にレモンがビタミンCの代表格として認知度が高いが、この中でもっともビタミンC含有量が高かったのは、、、である。

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