Publications by authors named "Ko Okumura"

412 Publications

Inhibition of Both Cyclooxygenase-1 and -2 Promotes Epicutaneous Th2 and Th17 Sensitization and Allergic Airway Inflammation on Subsequent Airway Exposure to Protease Allergen in Mice.

Int Arch Allergy Immunol 2021 Apr 19:1-12. Epub 2021 Apr 19.

Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Introduction: Epicutaneous (e.c.) allergen exposure is an important route of sensitization toward allergic diseases in the atopic march. Allergen sources such as house dust mites contain proteases that involve in the pathogenesis of allergy. Prostanoids produced via pathways downstream of cyclooxygenases (COXs) regulate immune responses. Here, we demonstrate effects of COX inhibition with nonsteroidal anti-inflammatory drugs (NSAIDs) on e.c. sensitization to protease allergen and subsequent airway inflammation in mice.

Methods: Mice were treated with NSAIDs during e.c. sensitization to a model protease allergen, papain, and/or subsequent intranasal challenge with low-dose papain. Serum antibodies, cytokine production in antigen-restimulated skin or bronchial draining lymph node (DLN) cells, and airway inflammation were analyzed.

Results: In e.c. sensitization, treatment with a nonspecific COX inhibitor, indomethacin, promoted serum total and papain-specific IgE response and Th2 and Th17 cytokine production in skin DLN cells. After intranasal challenge, treatment with indomethacin promoted allergic airway inflammation and Th2 and Th17 cytokine production in bronchial DLN cells, which depended modestly or largely on COX inhibition during e.c. sensitization or intranasal challenge, respectively. Co-treatment with COX-1-selective and COX-2-selective inhibitors promoted the skin and bronchial DLN cell Th cytokine responses and airway inflammation more efficiently than treatment with either selective inhibitor.

Conclusion: The results suggest that the overall effects of COX downstream prostanoids are suppressive for development and expansion of not only Th2 but also, unexpectedly, Th17 upon exposure to protease allergens via skin or airways and allergic airway inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000514975DOI Listing
April 2021

The Multifaceted Roles of EGFL7 in Cancer and Drug Resistance.

Cancers (Basel) 2021 Mar 1;13(5). Epub 2021 Mar 1.

Center for Genome and Regenerative Medicine, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-Ku, Tokyo 113-8421, Japan.

Invasion of cancer cells into surrounding tissue and the vasculature is an important step for tumor progression and the establishment of distant metastasis. The extracellular matrix (ECM) is home to many biomolecules that support new vessel formation and cancer growth. Endothelial cells release growth factors such as epidermal growth factor-like protein-7 (EGFL7), which contributes to the formation of the tumor vasculature. The signaling axis formed by EGFL7 and one of its receptors, beta 3 integrin, has emerged as a key mediator in the regulation of tumor metastasis and drug resistance. Here we summarize recent studies on the role of the ECM-linked angiocrine factor EGFL7 in primary tumor growth, neoangiogenesis, tumor metastasis by enhancing epithelial-mesenchymal transition, alterations in ECM rigidity, and drug resistance. We discuss its role in cellular adhesion and migration, vascular leakiness, and the anti-cancer response and provide background on its transcriptional regulation. Finally, we discuss its potential as a drug target as an anti-cancer strategy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13051014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957479PMC
March 2021

A possible association between a novel NLRP1 mutation and an autoinflammatory disease involving liver cirrhosis.

Hepatology 2021 Mar 19. Epub 2021 Mar 19.

Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

The nucleotide-binding domain leucine-rich repeat (LRR)-containing protein family pyrin domain (PYD)-containing protein 1 (NLRP1) forms an inflammasome complex with apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and caspase-1. Inflammasome-activated caspase-1 cleaves pro-IL-1β or pro-IL-18 to produce its mature form and induces a type of cell death called pyroptosis through gasdermin D (GSDMD) activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep.31818DOI Listing
March 2021

Anti-CD321 antibody immunotherapy protects liver against ischemia and reperfusion-induced injury.

Sci Rep 2021 Mar 18;11(1):6312. Epub 2021 Mar 18.

Juntendo Advanced Research Institute for Health Science, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

The prognosis of the liver transplant patients was frequently deteriorated by ischemia and reperfusion injury (IRI) in the liver. Infiltration of inflammatory cells is reported to play critical roles in the pathogenesis of hepatic IRI. Although T lymphocytes, neutrophils and monocytes infiltrated into the liver underwent IRI, we found that neutrophil depletion significantly attenuated the injury and serum liver enzyme levels in a murine model. Interestingly, the expression of CD321/JAM-A/F11R, one of essential molecules for transmigration of circulating leukocytes into inflammatory tissues, was significantly augmented on hepatic sinusoid endothelium at 1 h after ischemia and maintained until 45 min after reperfusion. The intraportal administration of anti-CD321 monoclonal antibody (90G4) significantly inhibited the leukocytes infiltration after reperfusion and diminished the damage responses by hepatic IRI (serum liver enzymes, inflammatory cytokines and hepatocyte cell death). Taken together, presented results demonstrated that blockade of CD321 by 90G4 antibody significantly attenuated hepatic IRI accompanied with substantial inhibition of leukocytes infiltration, particularly inhibition of neutrophil infiltration in the early phase of reperfusion. Thus, our work offers a potent therapeutic target, CD321, for preventing liver IRI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-85001-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973783PMC
March 2021

Interleukin-33 and thymic stromal lymphopoietin, but not interleukin-25, are crucial for development of airway eosinophilia induced by chitin.

Sci Rep 2021 Mar 15;11(1):5913. Epub 2021 Mar 15.

Graduate School of Integrated Sciences for Life, Hiroshima University, 1-4-4 Kagamiyama, Higashi-Hiroshima City, Hiroshima, 739-0046, Japan.

Exposure to various antigens derived from house dust mites (HDM) is considered to be a risk factor for development of certain allergic diseases such as atopic asthma, atopic dermatitis, rhinitis and conjunctivitis. Chitin is an insoluble polysaccharide (β-(1-4)-poly-N-acetyl-D-glucosamine) and a major component in the outer shell of HDMs. Mice exposed to chitin develop asthma-like airway eosinophilia. On the other hand, several lines of evidence show that the effects of chitin on immune responses are highly dependent on the size of chitin particles. In the present study, we show that chitin induced production of IL-33 and TSLP by alveolar and bronchial epithelial cells, respectively, in mice. IL-25, IL-33 and TSLP were reported to be important for group 2 innate lymphoid cell (ILC2)-, but not Th2 cell-, dependent airway eosinophilia in a certain model using chitin beads. Here, we show that-in our murine models-epithelial cell-derived IL-33 and TSLP, but not IL-25, were crucial for activation of resident lung Th2 cells as well as group 2 innate lymphoid cells (ILC2s) to produce IL-5, resulting in development of chitin-induced airway eosinophilia. Our findings provide further insight into the underlying mechanisms of development of HDM-mediated allergic disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-85277-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960735PMC
March 2021

The Multifaceted Role of Plasminogen in Cancer.

Int J Mol Sci 2021 Feb 25;22(5). Epub 2021 Feb 25.

Center for Genomic & Regenerative Medicine, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo 113-8421, Japan.

Fibrinolytic factors like plasminogen, tissue-type plasminogen activator (tPA), and urokinase plasminogen activator (uPA) dissolve clots. Though mere extracellular-matrix-degrading enzymes, fibrinolytic factors interfere with many processes during primary cancer growth and metastasis. Their many receptors give them access to cellular functions that tumor cells have widely exploited to promote tumor cell survival, growth, and metastatic abilities. They give cancer cells tools to ensure their own survival by interfering with the signaling pathways involved in senescence, anoikis, and autophagy. They can also directly promote primary tumor growth and metastasis, and endow tumor cells with mechanisms to evade myelosuppression, thus acquiring drug resistance. In this review, recent studies on the role fibrinolytic factors play in metastasis and controlling cell-death-associated processes are presented, along with studies that describe how cancer cells have exploited plasminogen receptors to escape myelosuppression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22052304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956603PMC
February 2021

Intractable Itch in Atopic Dermatitis: Causes and Treatments.

Biomedicines 2021 Feb 25;9(3). Epub 2021 Feb 25.

Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.

Itch or pruritus is the hallmark of atopic dermatitis and is defined as an unpleasant sensation that evokes the desire to scratch. It is also believed that itch is a signal of danger from various environmental factors or physiological abnormalities. Because histamine is a well-known substance inducing itch, H-antihistamines are the most frequently used drugs to treat pruritus. However, H-antihistamines are not fully effective against intractable itch in patients with atopic dermatitis. Given that intractable itch is a clinical problem that markedly decreases quality of life, its treatment in atopic dermatitis is of high importance. Histamine-independent itch may be elicited by various pruritogens, including proteases, cytokines, neuropeptides, lipids, and opioids, and their cognate receptors, such as protease-activated receptors, cytokine receptors, Mas-related G protein-coupled receptors, opioid receptors, and transient receptor potential channels. In addition, cutaneous hyperinnervation is partly involved in itch sensitization in the periphery. It is believed that dry skin is a key feature of intractable itch in atopic dermatitis. Treatment of the underlying conditions that cause itch is necessary to improve the quality of life of patients with atopic dermatitis. This review describes current insights into the pathophysiology of itch and its treatment in atopic dermatitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biomedicines9030229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996203PMC
February 2021

Epicutaneous vaccination with protease inhibitor-treated papain prevents papain-induced Th2-mediated airway inflammation without inducing Th17 in mice.

Biochem Biophys Res Commun 2021 Mar 19;546:192-199. Epub 2021 Feb 19.

Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Environmental allergen sources such as house dust mites contain proteases, which are frequently allergens themselves. Inhalation with the exogenous proteases, such as a model of protease allergen, papain, to airways evokes release and activation of IL-33, which promotes innate and adaptive allergic airway inflammation and Th2 sensitization in mice. Here, we examine whether epicutaneous (e.c.) vaccination with antigens with and without protease activity shows prophylactic effect on the Th airway sensitization and Th2-medated airway inflammation, which are driven by exogenous or endogenous IL-33. E.c. vaccination with ovalbumin restrained ovalbumin-specific Th2 airway sensitization and/or airway inflammation on subsequent inhalation with ovalbumin plus papain or ovalbumin plus recombinant IL-33. E.c. vaccination with papain or protease inhibitor-treated papain restrained papain-specific Th2 and Th9 airway sensitization, eosinophilia, and infiltration of IL-33-responsive Th2 and group 2 innate lymphoid cells on subsequent inhalation with papain. However, e.c. vaccination with papain but not protease inhibitor-treated papain induced Th17 response in bronchial draining lymph node cells. In conclusions, we demonstrated that e.c. allergen vaccination via intact skin in mice restrained even protease allergen-activated IL-33-driven airway Th2 sensitization to attenuate allergic airway inflammation and that e.c. vaccination with protease allergen attenuated the airway inflammation similar to its derivative lacking the protease activity, although the former but not the latter promoted Th17 development. In addition, the present study suggests that modified allergens, of which Th17-inducing e.c. adjuvant activity such as the protease activity was eliminated, might be preferable for safer clinical applications of the e.c. allergen administration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2020.12.090DOI Listing
March 2021

Elements of Immunoglobulin E Network Associate with Aortic valve Area in Patients with Acquired Aortic Stenosis.

Biomedicines 2020 Dec 31;9(1). Epub 2020 Dec 31.

Krakow Center for Medical Research and Technology, John Paul II Hospital, 31-202 Krakow, Poland.

Allergic mechanisms are likely involved in atherosclerosis and its clinical presentations, such as coronary artery disease (CAD). It has been previously reported that CAD severity associates with serum levels of immunoglobulin E (IgE), the molecule that, along with its high-affinity receptor (FcԑRI), plays a central role in allergic reactions. Considering multiple pathophysiological similarities between atherosclerosis and acquired aortic (valve) stenosis (AS), we speculated that allergic pathways could also contribute to the AS mechanisms and grading. To validate this hypothesis, we first checked whether total serum IgE levels associate with echocardiographic markers of AS severity. Having found a positive correlation between serum IgE and aortic valve area (AVA), we further speculated that also total IgE-determining genetic polymorphisms in , a locus encoding an allergen-biding FcԑRI subunit, are related to acquired AS severity. Indeed, the major allele of rs2251746 polymorphism, known to associate with higher IgE levels, turned out to correlate with larger AVA, a marker of less severe AS. Our findings surprisingly suggest a protective role of IgE pathways against AS progression. IgE-mediated protective mechanisms in AS require further investigations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biomedicines9010023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824289PMC
December 2020

Exogenous factors in the pathogenesis of atopic dermatitis: Irritants and cutaneous infections.

Clin Exp Allergy 2021 Mar 14;51(3):382-392. Epub 2021 Jan 14.

Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Atopic dermatitis (AD) is a chronic relapsing inflammatory cutaneous disease that is often associated with other atopic symptoms, such as food allergy, allergic rhinitis and asthma, leading to significant morbidity and healthcare costs. The pathogenesis of AD is complicated and multifactorial. Although the aetiology of AD remains incompletely understood, recent studies have provided further insight into AD pathophysiology, demonstrating that the interaction among genetic predisposition, immune dysfunction and environmental provocation factors contributes to its development. However, the increasing prevalence of AD suggests that environmental factors such as irritation and cutaneous infection play a crucial role in triggering and/or aggravating the disease. Of note, AD skin is susceptible to bacterial, fungal and viral infections, and microorganisms may colonize the skin and aggravate AD symptoms. Overall, understanding the mechanisms by which these risk factors affect the cutaneous immunity of patients with AD is of great importance for developing a precision medicine approach for treatment. This review summarizes recent developments in exogenous factors involved in the pathogenesis of AD, with special emphasis on irritants and microbial infections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cea.13820DOI Listing
March 2021

A Clinical Trial With Adoptive Transfer of Ex Vivo-induced, Donor-specific Immune-regulatory Cells in Kidney Transplantation-A Second Report.

Transplantation 2020 11;104(11):2415-2423

Department of Transplant Surgery, Mita Hospital, International University of Health and Welfare, Tokyo, Japan.

Background: Although the outcome of kidney transplantation (KTx) has improved, various adverse effects of immunosuppressants and chronic rejection aggravate the long-term prognosis of patients. Therefore, the induction of immune tolerance may be an effective therapeutic strategy.

Methods: A clinical trial aiming at immune tolerance induction was conducted in kidney transplant recipients from HLA mismatched living donors by infusing autologous donor-specific regulatory T cells (Treg). To obtain Treg, recipient's peripheral blood mononuclear cells were cocultured with irradiated donor cells in the presence of anti-CD80/CD86 monoclonal antibody for 2 weeks. For preconditioning, splenectomy + cyclophosphamide (CP) was employed in the first series (group A; n = 9). In group B, splenectomy was substituted by preadministration of rituximab (group B; n = 3). In the latest cases, rituximab + rabbit antithymocyte globulin was administered instead of cyclophosphamide (group C; n = 4). Twelve days after KTx, the cultured cells were intravenously infused, and immunosuppressants were gradually tapered thereafter.

Results: Although mixed lymphocyte reaction was remarkably suppressed in a donor-specific fashion, 6 out of 9 patients from group A, 1 out of 3 from group B, and 1 out of 4 from group C developed acute rejection within 1 year after KTx. Complete cessation of immunosuppression was not achieved, and a small dose of immunosuppressants was continued.

Conclusions: The adoptive transfer of autologous ex vivo-expanded Treg is 1 of the options to possibly induce alloimmune hyporesponsiveness. However, in the present study, further regimen optimization is still required and should be the focus of future investigations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TP.0000000000003149DOI Listing
November 2020

Role of Antimicrobial Peptides in Skin Barrier Repair in Individuals with Atopic Dermatitis.

Int J Mol Sci 2020 Oct 14;21(20). Epub 2020 Oct 14.

Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.

Atopic dermatitis (AD) is a common chronic inflammatory skin disease that exhibits a complex interplay of skin barrier disruption and immune dysregulation. Patients with AD are susceptible to cutaneous infections that may progress to complications, including staphylococcal septicemia. Although most studies have focused on filaggrin mutations, the physical barrier and antimicrobial barrier also play critical roles in the pathogenesis of AD. Within the physical barrier, the stratum corneum and tight junctions play the most important roles. The tight junction barrier is involved in the pathogenesis of AD, as structural and functional defects in tight junctions not only disrupt the physical barrier but also contribute to immunological impairments. Furthermore, antimicrobial peptides, such as LL-37, human b-defensins, and S100A7, improve tight junction barrier function. Recent studies elucidating the pathogenesis of AD have led to the development of barrier repair therapy for skin barrier defects in patients with this disease. This review analyzes the association between skin barrier disruption in patients with AD and antimicrobial peptides to determine the effect of these peptides on skin barrier repair and to consider employing antimicrobial peptides in barrier repair strategies as an additional approach for AD management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21207607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589391PMC
October 2020

Rising obstacle in a one-layer granular bed induced by continuous vibrations: two dynamical regimes governed by vibration velocity.

Soft Matter 2020 Sep;16(37):8612-8617

Physics Department and Soft Matter Center, Ochanomizu University, Tokoyo 112-8610, Japan.

The rising motion of an obstacle in a vibrated granular medium is a classic problem of granular segregation, and called the Brazil nut (BN) effect. Identification of the controlling vibration parameters of the effect is a long-standing problem. The simple possibility that the BN effect can be characterized solely by vibration velocity has recently been pointed out. The issue has become controversial over the long history of research, with only a few systems providing evidence for this simple possibility. Here, we investigate the rising motion of an obstacle in a vertically positioned one-layer granular bed under continuous vibrations. We find the rising motion is composed of two distinct regimes, and the first and second regimes are both governed, in terms of vibration parameters, solely by the vibration velocity. We further demonstrate simple scaling laws that well describe the two regimes. Our results support the emergent simple possibility for the controlling parameters of the BN effect and suggest that this feature could be universal. We propose two possible mechanisms of convection and arch effect for the two distinct regimes and demonstrate that these mechanisms explain the scaling laws followed by our experimental data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0sm01021aDOI Listing
September 2020

Critical role of IL-33, but not IL-25 or TSLP, in silica crystal-mediated exacerbation of allergic airway eosinophilia.

Biochem Biophys Res Commun 2020 12 22;533(3):493-500. Epub 2020 Sep 22.

Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, 739-8528, Japan; Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan; Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama, 332-0012, Japan. Electronic address:

Silica crystals (silica), which are a major mineral component of volcanic ash and desert dust, contribute to the pathogenesis of pulmonary disorders such as asthma and fibrosis. Although administration of silica or sand dust to rodents exacerbates development of ovalbumin-induced or house dust mite-induced asthma-like airway inflammation, the detailed mechanisms remain unclear. Here, using murine models, we found that silica can induce IL-33 expression in pulmonary epithelial cells. IL-33, but not IL-25 or TSLP, and type 2 cytokines such as IL-5 and IL-13 were critically involved in silica's exacerbation of OVA-induced airway eosinophilia in mice. Innate lymphoid cells (ILCs), but not T, B or NKT cells, were also involved in the setting. Moreover, a scavenger receptor that recognized silica was important for silica's exacerbating effect. These observations suggest that IL-33 induced in epithelial cells by silica activates ILCs to produce IL-5 and/or IL-13, contributing to silica's exacerbation of OVA-induced airway eosinophilia in mice. Our findings provide new insight into the underlying mechanisms of exacerbation of pulmonary disorders such as asthma following inhalation of silica-containing materials such as volcanic ash and desert dust.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2020.09.046DOI Listing
December 2020

Interaction between functional polymorphisms in FCER1A and TLR2 and the severity of atopic dermatitis.

Hum Immunol 2020 Dec 1;81(12):709-713. Epub 2020 Sep 1.

Krakow Center for Medical Research and Technology, John Paul II Hospital, Krakow, Poland; Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski Krakow University, Krakow, Poland. Electronic address:

Dendritic cell toll-like receptors (TLRs) and the high-affinity immunoglobulin E (IgE) receptor (FcεRI) may biologically interact with regard to atopic dermatitis (AD) development and, especially, severity. Our aim here was to test if such interaction can be detected on the genetic level. The combined effect of the TLR2 gene (TLR2) rs4696480 and the FcεRI α-chain gene (FCER1A) rs2252226 and rs2251746 polymorphisms on the AD severity as measured by SCORAD was assessed. The FCER1A rs2252226 and TLR2 rs4696480 polymorphisms interacted with regard to SCORAD. Higher SCORAD was observed in patients being the TLR2 rs4696480 major homozygotes and carrying at the same time the FCER1A rs2252226 minor allele, compared to those characterized by (any other of) the remaining combined rs2252226 and rs4696480 genotypes. The observation of the epistatic effect of TLR2 and FCER1A genetic variants on SCORAD is in line with the involvement of the interaction TLRs-FcεRI in the pathophysiology of AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humimm.2020.08.002DOI Listing
December 2020

Capillary Replacement in a Tube Prefilled with a Viscous Fluid.

Langmuir 2020 Sep 8;36(37):10952-10959. Epub 2020 Sep 8.

Physics Department and Soft Matter Center, Ochanomizu University, Tokyo 112-8610, Japan.

Capillary invasion of a liquid into an empty tube, which is called capillary rise when the tube axis is in the vertical direction, is one of the fundamental phenomena representing capillary effects. Usually, the tube is filled with another pre-existing fluid, air, whose viscosity and inertia can be practically neglected. In this study, we considered the effect of the pre-existing fluid, when its viscosity is non-negligible, in a horizontal geometry. We observed the dynamics when a capillary tube that is submerged horizontally in a liquid gets in contact with a second liquid. An appropriate combination of liquids allowed us to observe that the second liquid replaces the first without any prewetting process, thanks to a careful cleaning of capillary tubes. As a result, we experimentally observed three distinct viscous dynamics: (i) the conventional slowing-down dynamics, (ii) an unusual accelerating dynamics, and (iii) another unusual dynamics, which is linear in time. We derived a simple unified expression describing the three distinct dynamics, which accounts well for the observations. We also demonstrated a thorough experimental confirmation on the initial velocity of the replacement and the replacement time, the time required for the invading fluid to completely replace the pre-existing fluid in the horizontal geometry.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.langmuir.0c01612DOI Listing
September 2020

Notch signaling contributes to the establishment of sustained unresponsiveness to food allergens by oral immunotherapy.

J Allergy Clin Immunol 2021 Mar 24;147(3):1063-1076.e9. Epub 2020 Jul 24.

Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Background: Oral immunotherapy (OIT) aims to establish desensitization and sustained unresponsiveness (SU) in patients with food allergy by ingestion of gradually increasing doses of specific food allergens. However, little is known about the mechanisms by which OIT induces SU to specific allergens.

Objectives: We investigated the role of Notch signaling, which controls cell fate decisions in many types of immune cells in the induction of SU by OIT treatment.

Methods: Two types of mouse models, ovalbumin-induced food allergy and OIT, were generated. To elucidate the role of Notch signaling in OIT-induced SU, mice were intraperitoneally injected with the Notch signaling inhibitor N-[(3,5-difluorophenyl)acetyl]-l-alanyl-2-phenylglycine-1,1-dimethylethyl ester during the OIT treatment period.

Results: Ovalbumin-sensitized mice were desensitized and also had SU induced by OIT treatment, whereas repeated challenges with ovalbumin caused the development of severe allergic reactions in ovalbumin-sensitized mice. Administration of N-[(3,5-difluorophenyl)acetyl]-l-alanyl-2-phenylglycine-1,1-dimethylethyl ester to mice during the OIT treatment period inhibited the establishment of SU to ovalbumin but did not affect the induction of desensitization. OIT induced a systemic expansion of IL-10-producing CD4 T cells, including T2 cells, and myeloid-derived suppressor cells (MDSCs), particularly the monocytic MDSC subpopulation. Inhibition of Notch signaling prevented the OIT-induced expansion of those cells. In vitro cultures of bone marrow cells showed that Notch signaling directly promoted the generation of monocytic MDSCs. In addition, the contribution of MDSCs to OIT-induced SU was confirmed by MDSC depletion with the anti-Gr1 antibody.

Conclusion: Notch signaling contributes to the establishment of SU induced by OIT through systemic expansion of immunosuppressive cells, such as IL-10-producing CD4 T cells and MDSCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2020.07.011DOI Listing
March 2021

TSLP is a negative regulator of RANKL-induced osteoclastogenesis.

Biochem Biophys Res Commun 2020 09 26;530(3):508-512. Epub 2020 Jun 26.

Oral Health Science Center, Tokyo Dental College, Tokyo, 101-0061, Japan; Tokyo Dental College Research Branding Project, Tokyo Dental College, Tokyo, 101-0061, Japan; Department of Biochemistry, Tokyo Dental College, Tokyo, 101-0061, Japan.

Thymic stromal lymphopoietin (TSLP) is a member of the IL-2 cytokine family, which is known to activate type 2 innate lymphoid cells, mast cells, and Th2 cells; this activation results in allergic inflammation and host defense against parasites. TSLP has also been shown to promote Th17-mediated immune responses, such as those observed in the development of rheumatoid arthritis; however, its role in osteoclastogenesis remains poorly understood. Here, we investigated the functional involvement of TSLP in RANKL-induced osteoclast differentiation from murine bone marrow-derived macrophages (BMMs). Both RANK and RANK macrophages expressed TSLP receptor (TSLPR), while RANK osteoclast precursors maintained TSLPR expression after RANKL stimulation. TSLP stimulation led to inhibition of RANK-induced osteoclast differentiation in wild-type BMMs, but not Tslpr BMMs; TSLP stimulation also led to suppression of osteoclastogenic gene expression (Nfatc1, Acp5, Mmp9, and Ctsk). These inhibitory effects of TSLP were significantly reduced following STAT1 inhibition. Finally, we found that LPS stimulation induced TSLP production in murine calvarial osteoblasts, but not BMMs. Together, these observations suggest that TSLP acts directly on osteoclast precursors to suppress osteoclastogenesis. Osteoblasts, along with other TSLP-producing cells, may therefore contribute to the inhibition of osteoclastogenesis under inflammatory conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2020.05.055DOI Listing
September 2020

Innate IL-17A Enhances IL-33-Independent Skin Eosinophilia and IgE Response on Subcutaneous Papain Sensitization.

J Invest Dermatol 2021 Jan 26;141(1):105-113.e14. Epub 2020 May 26.

Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan. Electronic address:

IL-33-activated group 2 innate lymphoid cells critically contribute to protease allergen-induced airway inflammation models. However, IL-33 is dispensable for a subcutaneous (s.c.) papain-induced skin inflammation model, suggesting distinct mechanisms between intranasal and s.c. sensitization. Here, we examined the role of IL-17A in the s.c. model. Papain-exposed skin produced IL-17A and an excess amount of a soluble decoy receptor for IL-33, with the latter being a possible reason for the independence of the s.c. model from IL-33. An IL-17A deficiency attenuated papain-induced skin eosinophilia and serum papain-specific IgE and IgG1 levels, whereas the s.c. administration of IL-17A with enzymatically inactive papain enhanced serum papain-specific IgE and IgG1 levels and T helper 2 development in draining lymph nodes in an IL-33-independent manner, suggesting IL-33-independent enhancement of papain-specific type 2 responses by IL-17A. The s.c. papain increased IL-17A γδ T cells in draining lymph nodes, approximately half of which were Vγ4, as the majority of IL-17A cells, and increased Vγ5 and Vγ4 γδ T cells in the skin. Depletion of γδ TCR cells reduced T helper cytokine production in antigen-restimulated draining lymph node cells. These results suggest a novel role for IL-17A as an enhancer of skin eosinophilia and serum antigen-specific IgE production and for γδ T cells as an enhancer of T helper cell activation in the s.c. papain model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jid.2020.05.088DOI Listing
January 2021

Impact of maternal dietary gut microbial metabolites on an offspring's systemic immune response in mouse models.

Biosci Microbiota Food Health 2020 25;39(2):33-38. Epub 2020 Jan 25.

Department of Gastroenterology, School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.

The gut microbiota has a great impact on the host immune systems. Recent evidence suggests that the maternal gut microbiota affects the immune systems of offspring. Metabolites produced by the gut microbiota play crucial roles in the immune system. Previous studies have also revealed that metabolites such as short-chain fatty acids (SCFAs) and the aryl hydrocarbon receptor (AhR) ligands are involved in host health and diseases. Great progress has been made in understanding the roles of diet-derived SCFAs in the offspring's immune system. The findings to date raise the possibility that maternal dietary soluble fiber intake may play a role in the development of the offspring's systemic immune response. In this review, we summarize the present knowledge and discuss future therapeutic possibilities for using dietary soluble fiber intake against inflammatory diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12938/bmfh.19-013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162694PMC
January 2020

Inhibition of Importin β1 Augments the Anticancer Effect of Agonistic Anti-Death Receptor 5 Antibody in TRAIL-resistant Tumor Cells.

Mol Cancer Ther 2020 05 10;19(5):1123-1133. Epub 2020 Mar 10.

Department of Biofunctional Microbiota, Juntendo University Graduate School of Medicine, Tokyo, Japan.

TNF-related apoptosis-inducing ligand (TRAIL) and an agonistic antibody against the death-inducing TRAIL receptor 5, DR5, are thought to selectively induce tumor cell death and therefore, have gained attention as potential therapeutics currently under investigation in several clinical trials. However, some tumor cells are resistant to TRAIL/DR5-induced cell death, even though they express DR5. Previously, we reported that DR5 is transported into the nucleus by importin β1, and knockdown of importin β1 upregulates cell surface expression of DR5 resulting in increased TRAIL sensitivity Here, we examined the impact of importin β1 knockdown on agonistic anti-human DR5 (hDR5) antibody therapy. Drug-inducible importin β1 knockdown sensitizes HeLa cells to TRAIL-induced cell death , and exerts an antitumor effect when combined with agonistic anti-hDR5 antibody administration Therapeutic importin β1 knockdown, administered via the atelocollagen delivery system, as well as treatment with the importin β inhibitor, importazole, induced regression and/or eradication of two human TRAIL-resistant tumor cells when combined with agonistic anti-hDR5 antibody treatment. Thus, these findings suggest that the inhibition of importin β1 would be useful to improve the therapeutic effects of agonistic anti-hDR5 antibody against TRAIL-resistant cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-19-0597DOI Listing
May 2020

IL-25 exacerbates autoimmune aortitis in IL-1 receptor antagonist-deficient mice.

Sci Rep 2019 11 19;9(1):17067. Epub 2019 Nov 19.

Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.

IL-25, a member of the IL-17 family of cytokines, is known to enhance type 2 immune responses, but suppress type 3 (IL-17A)-mediated immune responses. Mice deficient in IL-1 receptor antagonist (Il1rn mice) have excessive IL-1 signaling, resulting in spontaneous development of IL-1-, TNF- and IL-17A-dependent aortitis. We found that expression of II25 mRNA was increased in the aortae of Il1rn mice, suggesting that IL-25 may suppress development of IL-1-, TNF- and IL-17A-dependent aortitis in Il1rn mice by inhibiting type 3-mediated immune responses. However, we unexpectedly found that Il25Il1rn mice showed attenuated development of aortitis, accompanied by reduced accumulation of inflammatory cells such as dendritic cells, macrophages and neutrophils and reduced mRNA expression of Il17a and Tnfa-but not Il4 or Il13-in local lesions compared with Il1rn mice. Tissue-, but not immune cell-, derived IL-25 was crucial for development of aortitis. IL-25 enhanced IL-1β and TNF production by IL-25 receptor-expressing dendritic cells and macrophages, respectively, at inflammatory sites of aortae of Il1rn mice, contributing to exacerbation of development of IL-1-, TNF- and IL-17A-dependent aortitis in those mice. Our findings suggest that neutralization of IL-25 may be a potential therapeutic target for aortitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-53633-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864066PMC
November 2019

Oxidative stress-responsive apoptosis inducing protein (ORAIP) plays a critical role in cerebral ischemia/reperfusion injury.

Sci Rep 2019 09 18;9(1):13512. Epub 2019 Sep 18.

Department of Biofunctional Microbiota, Juntendo University School of Medicine, Tokyo, Japan.

Oxidative stress is known to play a critical role in the pathogenesis of various disorders, especially in ischemia/reperfusion (I/R) injury. We identified an apoptosis-inducing humoral factor and named this novel post translationally modified secreted form of eukaryotic translation initiation factor 5A (eIF5A) "oxidative stress-responsive apoptosis inducing protein" (ORAIP). The purpose of this study was to investigate the role of ORAIP in the mechanisms of cerebral I/R injury. Hypoxia/reoxygenation induced expression of ORAIP in cultured rat cerebral neurons, resulting in extensive apoptosis of these cells, which was largely suppressed by neutralizing anti-ORAIP monoclonal antibody (mAb) in vitro. Recombinant-ORAIP induced extensive apoptosis of cerebral neurons. Cerebral I/R induced expression of ORAIP in many neurons in a rat tandem occlusion model in vivo. In addition, we analyzed the effects of intracerebroventricular administration of neutralizing anti-ORAIP mAb on the development of cerebral infarction. Cerebral I/R significantly increased ORAIP levels in cerebrospinal fluid. Treatment with intracerebroventricular administration of neutralizing anti-ORAIP mAb reduced infarct volume by 72%, and by 55% even when started after reperfusion. These data strongly suggest that ORAIP plays a pivotal role and will offer a critical therapeutic target for cerebral I/R injury induced by thrombolysis and thrombectomy for acute ischemic stroke.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-50073-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751213PMC
September 2019

Stromal fibroblasts induce metastatic tumor cell clusters via epithelial-mesenchymal plasticity.

Life Sci Alliance 2019 08 22;2(4). Epub 2019 Jul 22.

Department of Molecular Pathogenesis, Graduate School of Medicine, Juntendo University, Tokyo, Japan

Emerging evidence supports the hypothesis that multicellular tumor clusters invade and seed metastasis. However, whether tumor-associated stroma induces epithelial-mesenchymal plasticity in tumor cell clusters, to promote invasion and metastasis, remains unknown. We demonstrate herein that carcinoma-associated fibroblasts (CAFs) frequently present in tumor stroma drive the formation of tumor cell clusters composed of two distinct cancer cell populations, one in a highly epithelial (E-cadherinZEB1: E) state and another in a hybrid epithelial/mesenchymal (E-cadherinZEB1: E/M) state. The E cells highly express oncogenic cell-cell adhesion molecules, such as carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and CEACAM6 that associate with E-cadherin, resulting in increased tumor cell cluster formation and metastatic seeding. The E/M cells also retain associations with E cells, which follow the E/M cells leading to collective invasion. CAF-produced stromal cell-derived factor 1 and transforming growth factor-β confer the E and E/M states as well as invasive and metastatic traits via Src activation in apposed human breast tumor cells. Taken together, these findings indicate that invasive and metastatic tumor cell clusters are induced by CAFs via epithelial-mesenchymal plasticity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.26508/lsa.201900425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6653778PMC
August 2019

PU.1 plays a pivotal role in dendritic cell migration from the periphery to secondary lymphoid organs regulating CCR7 expression.

FASEB J 2019 10 17;33(10):11481-11491. Epub 2019 Jul 17.

Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Tokyo, Japan.

C-C chemokine receptor type 7 (CCR7) is essential for migration of dendritic cells (DCs) to draining lymph nodes. PU.1/ is a transcription factor playing a critical role in the gene regulation of DCs. PU.1 knockdown decreased the expression of CCR7 in bone marrow-derived DCs and subsequently attenuated migration and . Reporter assays, EMSA, and chromatin immunoprecipitation assays revealed that PU.1 binds to the most proximal Ets motif of the promoter, which is involved in transcriptional activation. The CCR7 expression level, which was higher in the programmed cell death 1 ligand 2 (PD-L2) population than in the PD-L2 population and was markedly suppressed by TGF-β treatment, coincided with the binding level of PU.1 to the promoter. The PU.1 binding level in CCR7 mesenteric lymph nodes DCs was higher than in other DC subtypes. The involvement of PU.1 in the expression of the gene was also observed in human DCs. We conclude that PU.1 plays a pivotal role in DC migration by transactivating the gene the Ets motif in the promoter in both humans and mice.-Yashiro, T., Takeuchi, H., Nakamura, S., Tanabe, A., Hara, M., Uchida, K., Okumura, K., Kasakura, K., Nishiyama, C. PU.1 plays a pivotal role in dendritic cell migration from the periphery to secondary lymphoid organs regulating CCR7 expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.201900379RRDOI Listing
October 2019

Antimicrobial peptide derived from insulin-like growth factor-binding protein 5 activates mast cells via Mas-related G protein-coupled receptor X2.

Allergy 2020 01 28;75(1):203-207. Epub 2019 Jul 28.

Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/all.13975DOI Listing
January 2020

Elevation of the vitreous body concentrations of oxidative stress-responsive apoptosis-inducing protein (ORAIP) in proliferative diabetic retinopathy.

Graefes Arch Clin Exp Ophthalmol 2019 Jul 6;257(7):1519-1525. Epub 2019 May 6.

Department of Ophthalmology, Diabetes Center, Tokyo Women's Medical University, Tokyo, Japan.

Purpose: Oxidative stress has been implicated in the pathogenesis of various disorders, including diabetic retinopathy (DR). Oxidative stress-responsive apoptosis-inducing protein (ORAIP; a tyrosine-sulfated secreted form of eukaryotic translation initiation factor 5A [eIF5A]) is a recently discovered pro-apoptotic ligand that is secreted from cells in response to oxidative stress and induces apoptosis in an autocrine fashion. This study aimed to determine if ORAIP plays a role in DR.

Methods: To investigate the role of ORAIP in DR, we analyzed the levels of ORAIP in the vitreous body and their relationship with the extent of proliferative diabetic retinopathy (PDR). Enzyme-linked immunosorbent assay was used to quantify the levels of ORAIP, vascular endothelial growth factor (VEGF), C-C motif chemokine ligand 2 (CCL2), interleukin-6 (IL-6), and IL-8 in the vitreous body of 40 eyes from 28 patients with PDR and 11 patients with non-PDR (NPDR). We also analyzed the expression of ORAIP in insoluble proliferative tissues from vitreous body samples by immunofluorescent staining.

Results: The vitreous body concentration of ORAIP was significantly (P = 0.0433) higher in the PDR group (52.26 ± 8.68 [mean ± SE] ng/mL, n = 29) than in the NPDR group (28.21 ± 7.30 ng/mL, n = 11). However, there were no significant correlations between the concentration of ORAIP and those of VEGF, IL-6, CCL2, or IL-8. ORAIP expression was observed in the insoluble proliferative tissues in vitreous body samples of most patients in the PDR group, whereas almost no expression of ORAIP was observed in patients in the NPDR group.

Conclusions: Our findings strongly suggest that ORAIP plays a role in oxidative stress-induced retinal injury and may be a sensitive diagnostic marker and a promising therapeutic target for oxidative stress-induced cytotoxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00417-019-04343-wDOI Listing
July 2019

CD155-Transducing Signaling through TIGIT Plays an Important Role in Transmission of Tolerant State and Suppression Capacity.

Immunohorizons 2018 11 16;2(10):338-348. Epub 2018 Nov 16.

Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan;

The precise mechanism of how the regulatory T cell population elicits and maintains tolerant state in activated T cells is poorly understood. To address this issue, we established an in vitro coculture system using mouse T cells and showed that tolerant state is serially passed from preinduced-tolerant T cells into new TCR-stimulated T cells across generations in a dendritic cell-independent manner. In this successive induction process of tolerant state, TIGIT was found to play an important role: TIGIT expression on induced-tolerant T cells was promoted in stimulated T cells cocultured with the tolerant cells. In addition, these stimulated T cells in the coculture also expressed high B lymphocyte-induced maturation protein 1 accompanied by IL-2 suppression. Because CD155, a partner of TIGIT, is known to transduce signaling inside by -interaction with its ligands, these phenotypical changes in TCR-stimulated naive T cells were reproduced when naive T cells were double cross-linked by CD3 and CD155. These results indicate that TIGIT enhanced on tolerant T cells may function as a ligand of its paired receptor CD155 to transduce signaling into its expressing naive T cells to accelerate new TIGIT expressions as well as IL-2 suppression via B lymphocyte-induced maturation protein 1 enhancement. In consideration of these results, we propose a novel process in which tolerant state in T cell population is maintained by successive generation of new tolerant T cells from naive T cells as one of the regulating mechanisms in immune responses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/immunohorizons.1800033DOI Listing
November 2018