Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Other Link： https://doi.org/10.2147/JBM.S9772

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publisher：Communications Biology  

Acute immune responses with excess production of cytokines, lipid/chemical mediators, or coagulation factors, often result in lethal damage. In addition, the innate immune system utilizes multiple types of receptors that recognize neurotransmitters as well as pathogen-associated molecular patterns, making immune responses complex and clinically unpredictable. We here report an innate immune and adrenergic link inducing lethal levels of platelet-activating factor. Injecting mice with toll-like receptor (TLR) 4 ligand lipopolysaccharide (LPS), cell wall N-glycans of Candida albicans, and the α2-adrenergic receptor (α2-AR) agonist medetomidine induces lethal damage. Knocking out the C-type lectin Dectin-2 prevents the lethal damage. In spleen, large amounts of platelet-activating factor (PAF) are detected, and knocking out lysophospholipid acyltransferase 9 (LPLAT9/LPCAT2), which encodes an enzyme that converts inactive lyso-PAF to active PAF, protects mice from the lethal damage. These results reveal a linkage/crosstalk between the nervous and the immune system, possibly inducing lethal levels of PAF.

DOI： 10.1038/s42003-024-06498-7

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Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.heliyon.2024.e38139

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Language：English   Publishing type：Research paper (scientific journal)  

The generation and maintenance of memory T cells are regulated by various factors, including cytokines. Previous studies have shown that IL-27 is produced during the early acute phase of Plasmodium chabaudi chabaudi AS (Pcc) infection and inhibits the development of Th1-type memory CD4+ T cells. However, whether IL-27 acts directly on its receptor on Plasmodium-specific CD4+ T cells or indirectly via its receptor on other immune cells remains unclear. We aimed to determine the role of IL-27 receptor signaling in different immune cell types in regulating the generation and phenotype of memory CD4+ T cells during Plasmodium infection. We utilized Plasmodium-specific TCR transgenic mice, PbT-II, and Il27rα-/- mice to assess the direct and indirect effects of IL-27 signaling on memory CD4+ T-cell generation. Mice were transferred with PbT-II or Il27rα-/- PbT-II cells and infected with Pcc. Conditional knockout mice lacking the IL-27 receptor in T cells or dendritic cells were employed to discern the specific immune cell types involved in IL-27 receptor signaling. High levels of memory in PbT-II cells with Th1-shift occurred only when both PbT-II and host cells lacked the IL-27 receptor, suggesting the predominant inhibitory role of IL-27 signaling in both cell types. Furthermore, IL-27 receptor signaling in T cells limited the number of memory CD4+ T cells, while signaling in both T and dendritic cells contributed to the Th1 dominance of memory CD4+ T cells. These findings underscore the complex cytokine signaling network regulating memory CD4+ T cells during Plasmodium infection.

DOI： 10.1093/intimm/dxae039

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Language：English   Publishing type：Research paper (scientific journal)  

Cryptococcus deneoformans is a yeast-type fungus that causes fatal meningoencephalitis in immunocompromised patients and evades phagocytic cell elimination through an escape mechanism. Memory T (Tm) cells play a central role in preventing the reactivation of this fungal pathogen. Among these cells, tissue-resident memory T (TRM) cells quickly respond to locally invaded pathogens. This study analyzes the kinetics of effector T (Teff) cells and Tm cells in the lungs after cryptococcal infection. Emphasis is placed on the kinetics and cytokine expression of TRM cells in the early phase of infection. CD4+ Tm cells exhibited a rapid increase by day 3, peaked at day 7, and then either maintained their levels or exhibited a slight decrease until day 56. In contrast, CD8+ Tm cells reached their peak on day 3 and thereafter decreased up to day 56 post-infection. These Tm cells were predominantly composed of CD69+ TRM cells and CD69+ CD103+ TRM cells. Disruption of the CARD9 gene resulted in reduced accumulation of these TRM cells and diminished interferon (IFN) -γ expression in TRM cells. TRM cells were derived from T cells with T cell receptors non-specific to ovalbumin in OT-II mice during cryptococcal infection. In addition, TRM cells exhibited varied behavior in different tissues. These results underscore the importance of T cells, which produce IFN-γ in the lungs during the early stage of infection, in providing early protection against cryptococcal infection through CARD9 signaling.

DOI： 10.1128/iai.00024-24

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Language：Japanese  

DOI： 10.14952/seikagaku.2023.950618

Language：English   Publishing type：Research paper (scientific journal)  

Optimal conditions for wound healing require a smooth transition from the early stage of inflammation to proliferation, and during this time alternatively activated (M2) macrophages play a central role. Recently, heat-killed lactic acid bacteria (LAB), such as Lactobacillus plantarum (L. plantarum) have been reported as possible modulators affecting the immune responses in wound healing. However, how signaling molecules regulate this process after the administration of heat-killed LAB remains unclear. In this study, we examined the effect of heat-killed L. plantarum KB131 (KB131) administration on wound healing and the contribution of CARD9, which is an essential signaling adaptor molecule for NF-kB activation upon triggering through C-type lectin receptors, in the effects of this bacterium. We analyzed wound closure, histological findings, and inflammatory responses. We found that administration of KB131 accelerated wound closure, re-epithelialization, granulation area, CD31-positive vessels, and α-SMA-positive myofibroblast accumulated area, as well as the local infiltration of leukocytes. In particular, M2 macrophages were increased, in parallel with CCL5 synthesis. The acceleration of wound healing responses by KB131 was canceled in CARD9-knockout mice. These results indicate that the topical administration of KB131 accelerates wound healing, accompanying increased M2 macrophages, which suggests that CARD9 may be involved in these responses.

DOI： 10.1038/s41598-023-42919-z

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Language：Japanese   Publisher：Japanese Pharmacological Society  

<p>Physiological itch is crucial for host defense because scratching behavior leads to removing potentially harmful organism from the skin. However, itch in chronic disease such as atopic dermatitis induces unpleasant effects. Recent studies have paid attention to type2 cytokines including IL-4, IL-13 and IL-31 as allergic dermatitis-associated itch mediators. Indeed, receptors of these cytokines are expressed on dorsal root ganglion neurons and the cytokines can activate and/or sensitize the neurons directly. However, immune regulation of itch sensation has not yet been fully understood.</p><p>IL-27 is an immunoregulatory cytokine which belongs to IL-12 cytokine family. IL-27 is mainly produced by antigen-presenting cells and transmits the signals via a heterodimeric receptor composed of IL-27 receptor a chain (WSX-1) and gp130. Although IL-27 suppresses Th2 and ILC2 responses, the role of IL-27 in neural system remains to be elucidated.</p><p>Here, we found that mice deficient in WSX-1 showed enhanced scratching behavior against several pruritogens. Conversely, administration of recombinant IL-27 suppressed pruritogen-induced scratching behavior in WT mice. This suppressive effect of IL-27 in itch sensation is abolished in Nav1.8-Cre WSX-1^flox/flox mice which lack sensory neuron specific WSX-1 expression. In addition, treatment with JAK kinase inhibitor abrogates the effect of IL-27 in scratching behavior. These results imply that IL-27 acts on sensory neuron and suppresses neuronal activity by JAK kinase-dependent manner, leading to regulatory function in itch sensation.</p>

DOI： 10.1254/jpssuppl.97.0_3-b-o09-3

Language：Japanese   Publisher：(株)ワールドプランニング  

Language：Japanese   Publisher：(株)ワールドプランニング  

Language：Japanese   Publisher：(一社)日本認知症学会  

Language：Japanese   Publisher：(一社)日本認知症学会  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

The rapid aging of the population makes the detection and prevention of frailty increasingly important. Oral frailty has been proposed as a novel frailty phenotype and is defined as a decrease in oral function coexisting with a decline in cognitive and physical functions. Oral frailty has received particular attention in relation to Alzheimer's disease (AD). However, the pathomechanisms of oral frailty related to AD remain unknown. It is assumed that the mesencephalic trigeminal nucleus (Vmes), which controls mastication, is affected by AD pathology, and as a result, masticatory function may be impaired. To investigate this possibility, we included male 3 × Tg-AD mice and their non-transgenic counterpart (NonTg) of 3–4 months of age in the present study. Immunohistochemistry revealed amyloid-β deposition and excessive tau phosphorylation in the Vmes of 3 × Tg-AD mice. Furthermore, vesicular glutamate transporter 1-immunopositive axon varicosities, which are derived from Vmes neurons, were significantly reduced in the trigeminal motor nucleus of 3 × Tg-AD mice. To investigate whether the AD pathology observed in the Vmes affects masticatory function, we analyzed electromyography of the masseter muscle during feeding. The 3 × Tg-AD mice showed a significant delay in masticatory rhythm compared to NonTg mice. Furthermore, we developed a system to simultaneously record bite force and electromyography of masseter, and devised a new method to estimate bite force during food chewing in mice. Since the muscle activity of the masseter showed a high correlation with bite force, it could be accurately estimated from the muscle activity. The estimated bite force of 3 × Tg-AD mice eating sunflower seeds was predominantly smaller than that of NonTg mice. However, there was no difference in masseter weight or muscle fiber cross-sectional area between the two groups, suggesting that the decreased bite force and delayed mastication rhythm observed in 3 × Tg-AD mice were not due to abnormality of the masseter. In conclusion, the decreased masticatory function observed in 3 × Tg-AD mice was most likely caused by AD pathology in the Vmes. Thus, novel quantitative analyses of masticatory function using the mouse model of AD enabled a comprehensive understanding of oral frailty pathogenesis.

DOI： 10.3389/fnagi.2022.935033

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

Abstract

Abstract

IL-17 plays important roles in host defense against Candida albicans at barrier surfaces and during invasive infection. However, the role of IL-17 in host defense after colonization of the epidermis, a main site of C. albicans infection, remains poorly understood. Using a murine model of epicutaneous candidiasis without skin abrasion, we found that skin inflammation triggered by epidermal C. albicans colonization was self-limiting with fungal clearance completed by day 7 after inoculation in wild-type mice or animals deficient in IL-17A or IL-17F. In contrast, marked neutrophilic inflammation in the epidermis and impaired fungal clearance were observed in mice lacking both IL-17A and IL-17F. Clearance of C. albicans was independent of Dectin-1, Dectin-2, CARD9 (caspase-recruitment domain family, member 9), TLR2 (Toll-like receptor 2) and MyD88 in the epidermal colonization model. We found that group 3 innate lymphoid cells (ILC3s) and γδT cells were the major IL-17 producers in the epicutaneous candidiasis model. Analyses of Rag2−/− mice and Rag2−/−Il2rg−/− mice revealed that production of IL-17A and IL-17F by ILC3s was sufficient for C. albicans clearance. Finally, we found that depletion of neutrophils impaired C. albicans clearance in the epidermal colonization model. Taken together, these findings indicate a critical and redundant function of IL-17A and IL-17F produced by ILC3s in host defense against C. albicans in the epidermis. The results also suggest that epidermal C. albicans clearance is independent of innate immune receptors or that these receptors act redundantly in fungal recognition and clearance.

DOI： 10.1093/intimm/dxac019

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Other Link： https://academic.oup.com/intimm/article-pdf/34/8/409/45068650/dxac019.pdf

Language：English   Publisher：日本細菌学会  

Language：English   Publishing type：Research paper (scientific journal)  

The cell walls and capsules of Cryptococcus neoformans, a yeast-type fungal pathogen, are rich in polysaccharides. Dectin-2 is a C-type lectin receptor (CLR) that recognizes high-mannose polysaccharides. Previously, we demonstrated that Dectin-2 is involved in cytokine production by bone marrow-derived dendritic cells (BM-DCs) in response to stimulation with C. neoformans. In the present study, we analyzed the role of Dectin-2 in the phagocytosis of C. neoformans by BM-DCs. The engulfment of this fungus by BM-DCs was significantly decreased in mice lacking Dectin-2 (Dectin-2KO) or caspase recruitment domain-containing protein 9 (CARD9KO), a common adapter molecule that delivers signals triggered by CLRs, compared to wild-type (WT) mice. Phagocytosis was likewise inhibited, to a similar degree, by the inhibition of Syk, a signaling molecule involved in CLR-triggered activation. A PI3K inhibitor, in contrast, completely abrogated the phagocytosis of C. neoformans. Actin polymerization, i.e., conformational changes in cytoskeletons detected at sites of contact with C. neoformans, was also decreased in BM-DCs of Dectin-2KO and CARD9KO mice. Finally, the engulfment of C. neoformans by macrophages was significantly decreased in the lungs of Dectin-2KO mice compared to WT mice. These results suggest that Dectin-2 may play an important role in the actin polymerization and phagocytosis of C. neoformans by DCs, possibly through signaling via CARD9 and a signaling pathway mediated by Syk and PI3K.

DOI： 10.1128/iai.00330-21

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Language：Japanese   Publisher：(公財)コーセーコスメトロジー研究財団  

アレルギー性化合物を感知するImmunoreceptor tyrosine-based activation motifs(ITAM)共役受容体の同定を試み、その受容体のアレルギー性接触皮膚炎(ACD)発症における役割を調べた。ITAM共役受容体-Igライブラリーを用いたハプテン結合試験を行った。その結果、異なるハプテンに対して結合性を示し、さらにITAM-NFATシグナルを活性化する受容体としてIgSFR2、IgSFR6の二つを同定した。両受容体の遺伝子欠損マウスを用いてTNCB誘導性のcontact hyper sensitivity(CHS)試験を実施した。その結果、対照マウス(DAP12欠損マウス)ではTNCBチャレンジ後の耳介の腫脹がほとんど生じないのに対し、IgSFR2およびIgSFR6欠損マウスは野生型マウスと同等の腫脹が観察された。この結果から、IgSFR2あるいはIgSFR6の単独の欠損はCHS発症には影響しないことが分かった。In vitroの結合試験において、IgSFR2およびIgSFR6のどちらもTNCBに結合性を示したことから、これらの受容体が協調的にTNCBの認識に関わっていたと考え、両方の受容体を欠損するマウス(IgSFR2/6-KO)を作成してCHS試験を実施した。しかし、IgSFR2/6-KOでも野生型マウスと同等のCHSの誘導が観察された。

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

Abstract

Ligand-induced cellular signaling involved in interleukin 10 (IL-10) production by lamina propria macrophages (LPMs) during their interactions with commensal bacteria is not clearly understood. We previously showed, using mice lacking a C-type lectin MGL1/CD301a, that this molecule on colonic LPMs plays an important role in the induction of IL-10 upon interaction with commensal bacteria, Streptococcus sp.

In the present report, we show that the physical engagement of MGL1/CD301a on LPMs with in-situ isolated Streptococcus sp. bacteria leads to IL-10 messenger RNA (mRNA) induction. Spleen tyrosine kinase (Syk), caspase recruitment domain 9 (CARD9) and extracellular signal-regulated kinase (ERK), but not NF-κB pathway, are shown to be indispensable for IL-10 mRNA induction after stimulation with heat-killed Streptococcus sp. Guanidine hydrochloride treatment of Streptococcus sp., which is known to extract bacterial cell surface glycan-rich components, abolished bacterial binding to recombinant MGL1/CD301a. The extract contained materials which bound rMGL1 in ELISA and appeared to induce IL-10 mRNA expression in LPMs in vitro. Lectin blotting showed that the extract contained glycoproteins that are considered as putative ligands for MGL1. Some human commensal Lactobacillus species also induced IL-10 mRNA expression by colonic LPMs in vitro, which depends on the presence of MGL1/CD301a and CARD9. The present results are the first to show that MGL1/CD301a acts as a signal transducer during colonic host–microbe interactions.

DOI： 10.1093/glycob/cwab015

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Other Link： http://academic.oup.com/glycob/article-pdf/31/7/827/39610830/cwab015.pdf

Publisher：Infection and Immunity  

DOI： 10.1128/IAI.00400-20

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Publisher：Heliyon  

DOI： 10.1016/j.heliyon.2020.e04064

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Publisher：International Immunology  

DOI： 10.1093/intimm/dxz063

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Publisher：Parasitology International  

DOI： 10.1016/j.parint.2019.101994

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Publisher：Journal of Alzheimer's Disease  

DOI： 10.3233/JAD-200257

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Publisher：(公財)上原記念生命科学財団  

Publisher：FASEB Journal  

DOI： 10.1096/fj.201900477RR

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Publisher：The Japanese Society for Cutaneous Immunology and Allergy  

<p>　Allergic contact dermatitis (ACD) is a delayed-type hypersensitivity skin reaction caused by T cells reactive to contact allergens, including metals, such as nickel and cobalt, and numerous chemical contact sensitizers termed haptens. Priming of T cells requires the maturation of antigen-presenting dendritic cells (DCs) by activation through innate immune pattern-recognition receptors. However, the innate immune mechanisms by which structurally varied haptens are sensed by and activate DCs are unclear. We recently reported that priming of hapten-specific T cells requires signaling through the IL-1R1-MyD88 pathway triggered by IL-1 released from hapten-stimulated DCs. Chemical contact sensitizers can trigger the activation of spleen tyrosine kinase (Syk) through immunoreceptor tyrosine-based activation motifs (ITAM) . Syk activation induces both CARD9/BCL10-dependent pro-IL-1 synthesis and ROS-dependent NLRP3 inflammasome activation, leading to the secretion of bioactive IL-1α and IL-1β by DCs. Thus, our study revealed an innate immune mechanism essential for contact sensitization to chemical allergens.</p>

DOI： 10.18934/jscia.2.2_272

Publisher：PLoS ONE  

DOI： 10.1371/journal.pone.0195119

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Publisher：Experimental Dermatology  

DOI： 10.1111/exd.13389

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Publisher：Clinical and Experimental Immunology  

DOI： 10.1111/cei.13002

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Publisher：Immunobiology  

DOI： 10.1016/j.imbio.2016.12.004

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Publisher：EBioMedicine  

DOI： 10.1016/j.ebiom.2016.11.015

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Language：English   Publishing type：Research paper (scientific journal)  

Event date： 2014.11

Language：Japanese  

Venue：那覇  

その他

Event date： 2014.10

Language：Japanese  

Venue：京都  

国内学会

Event date： 2014.5

Language：Japanese  

Venue：福岡  

国内学会

Presentation type：Oral presentation (general)  

Event date： 2022.6

Language：English   Presentation type：Oral presentation (invited, special)  

Event date： 2022.3

Presentation type：Symposium, workshop panel (nominated)  

Event date： 2021.11

Presentation type：Oral presentation (invited, special)  

Event date： 2013.8

Language：English  

Venue：Milano, Italy  

国際学会

Event date： 2013.8

Language：English  

Venue： Milano, Italy  

国際学会

Event date： 2013.8

Language：English  

Venue：Milano, Italy  

国際学会

Event date： 2013.5

Language：English  

Venue：Honolulu, Hawaii  

国際学会

Event date： 2013.2

Language：Japanese  

Venue：福岡  

その他

Event date： 2012.10

Language：English  

Venue：Tokyo, Japan  

国際学会

Event date： 2012.10

Language：English  

Venue：東京  

国際学会

Event date： 2012.3

Language：Japanese  

Venue：札幌  

国内学会

Presentation type：Symposium, workshop panel (nominated)  

Presentation type：Oral presentation (general)  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：English  

Language：English  

Language：Japanese  

Language：English  

Language：Japanese  

Language：Japanese  

Language：Japanese