Publications by authors named "Hajime Karasuyama"

131 Publications

E-cadherin is regulated by GATA-2 and marks the early commitment of mouse hematopoietic progenitors to the basophil and mast cell fates.

Sci Immunol 2021 02;6(56)

Division of Hematology/Oncology, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

E-cadherin is a calcium-dependent cell-cell adhesion molecule extensively studied for its involvement in tissue formation, epithelial cell behavior, and suppression of cancer. However, E-cadherin expression in the hematopoietic system has not been fully elucidated. Combining single-cell RNA-sequencing analyses and immunophenotyping, we revealed that progenitors expressing high levels of E-cadherin and contained within the granulocyte-monocyte progenitors (GMPs) fraction have an enriched capacity to differentiate into basophils and mast cells. We detected E-cadherin expression on committed progenitors before the expression of other reported markers of these lineages. We named such progenitors pro-BMPs (pro-basophil and mast cell progenitors). Using RNA sequencing, we observed transcriptional priming of pro-BMPs to the basophil and mast cell lineages. We also showed that GATA-2 directly regulates E-cadherin expression in the basophil and mast cell lineages, thus providing a mechanistic connection between the expression of this cell surface marker and the basophil and mast cell fate specification.
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http://dx.doi.org/10.1126/sciimmunol.aba0178DOI Listing
February 2021

[PREVIOUSLY-UNAPPRECIATED ROLES FOR BASOPHILS IN HEALTH AND DISEASE].

Arerugi 2020;69(10):964-967

TMDU Advanced Research Institute (TMDU-ARIS), Tokyo Medical and Dental University (TMDU).

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http://dx.doi.org/10.15036/arerugi.69.964DOI Listing
February 2021

Basophils and their effector molecules in allergic disorders.

Allergy 2020 Nov 18. Epub 2020 Nov 18.

Inflammation, Infection and Immunity Laboratory, TMDU Advanced Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

Basophils are the rarest granulocytes which represent <1% of peripheral blood leukocytes. Basophils bear several phenotypic similarities to tissue-resident mast cells and therefore had been erroneously considered as blood-circulating mast cells. However, recent researches have revealed that basophils play nonredundant roles in allergic inflammation, protective immunity against parasitic infections and regulation of innate and acquired immunity. Basophils are recruited to inflamed tissues and activated in an IgE-dependent or IgE-independent manner to release a variety of effector molecules. Such molecules, including IL-4, act on various types of cells and play versatile roles, including the induction and termination of allergic inflammation and the regulation of immune responses. Recent development of novel therapeutic agents has enabled us to gain further insights into basophil biology in human disorders. In this review, we highlight the recent advances in the field of basophil biology with a particular focus on the role of basophils in allergic inflammation. Further studies on basophils and their effector molecules will help us identify novel therapeutic targets for treating allergic disorders.
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http://dx.doi.org/10.1111/all.14662DOI Listing
November 2020

Immunobiology of Acquired Resistance to Ticks.

Front Immunol 2020 14;11:601504. Epub 2020 Oct 14.

Department of Cellular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.

Ticks are blood-sucking arthropods of great importance in the medical and veterinary fields worldwide. They are considered second only to mosquitos as vectors of pathogenic microorganisms that can cause serious infectious disorders, such as Lyme borreliosis and tick-borne encephalitis. Hard () ticks feed on host animals for several days and inject saliva together with pathogens to hosts during blood feeding. Some animal species can acquire resistance to blood-feeding by ticks after a single or repeated tick infestation, resulting in decreased weights and numbers of engorged ticks or the death of ticks in subsequent infestations. Importantly, this acquired tick resistance (ATR) can reduce the risk of pathogen transmission from pathogen-infected ticks to hosts. This is the basis for the development of tick antigen-targeted vaccines to forestall tick infestation and tick-borne diseases. Accumulation of basophils is detected in the tick re-infested skin lesion of animals showing ATR, and the ablation of basophils abolishes ATR in mice and guinea pigs, illustrating the critical role for basophils in the expression of ATR. In this review article, we provide a comprehensive overview of recent advances in our understanding of the cellular and molecular mechanisms responsible for the development and manifestation of ATR, with a particular focus on the role of basophils.
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http://dx.doi.org/10.3389/fimmu.2020.601504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591762PMC
October 2020

The role of basophils in acquired protective immunity to tick infestation.

Parasite Immunol 2020 Oct 30:e12804. Epub 2020 Oct 30.

Inflammation, Infection and Immunity Laboratory, TMDU Advanced Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

Ticks are blood-feeding ectoparasites that transmit a variety of pathogens to host animals and humans, causing severe infectious diseases such as Lyme disease. In a certain combination of animal and tick species, tick infestation elicits acquired immunity against ticks in the host, which can reduce the ability of ticks to feed on blood and to transmit pathogens in the following tick infestations. Therefore, our understanding of the cellular and molecular mechanisms of acquired tick resistance (ATR) can advance the development of anti-tick vaccines to prevent tick infestation and tick-borne diseases. Basophils are a minor population of white blood cells circulating in the bloodstream and are rarely observed in peripheral tissues under steady-state conditions. Basophils have been reported to accumulate at tick-feeding sites during re-infestation in cattle, rabbits, guinea pigs and mice. Selective ablation of basophils resulted in a loss of ATR in guinea pigs and mice, illuminating the essential role of basophils in the manifestation of ATR. In this review, we discuss the recent advance in the elucidation of the cellular and molecular mechanisms underlying basophil recruitment to the tick-feeding site and basophil-mediated ATR.
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http://dx.doi.org/10.1111/pim.12804DOI Listing
October 2020

Visualization of mechanical stress-mediated Ca signaling in the gut using intravital imaging.

Biosci Microbiota Food Health 2020 11;39(4):209-218. Epub 2020 Jun 11.

Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.

Mechanosensory systems have been implicated in the maintenance of gut homeostasis, but details on the related mechanisms are scarce. Recently, we generated a conditional Ca biosensor yellow cameleon 3.60 (YC3.60)-expressing transgenic mouse model and established a five-dimensional (5D; x, y, z, time, and Ca) intravital imaging system for investigating lymphoid tissues and enteric epithelial cell responses. To validate this gut-sensing system, we visualized responses of enteric nervous system (ENS) cells in Nestin-Cre/YC3.60 mice with specific YC3.60 expression. The ENS, including the myenteric (Auerbach's) and submucous (Meissner's) plexuses, could be visualized without staining in this mouse line, indicating that the probe produced sufficient fluorescent intensity. Furthermore, the myenteric plexus exhibited Ca signaling during peristalsis without stimulation. Nerve endings on the surface of enteric epithelia also exhibited Ca signaling without stimulation. Mechanical stress induced transient salient Ca flux in the myenteric plexus and in enteric epithelial cells in the Nestin-Cre/YC3.60 and the CAG-Cre/YC3.60 lines, respectively. Furthermore, the potential TRPM7 inhibitors were shown to attenuate mechanical stress-mediated Ca signaling. These data indicate that the present intravital imaging system can be used to visualize mechanosensory Ca signaling in ENS cells and enteric epithelial cells.
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http://dx.doi.org/10.12938/bmfh.2019-054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573108PMC
June 2020

Skin-infiltrating basophils promote atopic dermatitis-like inflammation via IL-4 production in mice.

Allergy 2020 10 26;75(10):2613-2622. Epub 2020 May 26.

Department of Immune Regulation, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

Background: Patients with atopic dermatitis (AD) often show the infiltration of basophils in the affected skin. Because basophils represent only a minor fraction among cellular infiltrates in the skin lesion, the functional significance of skin-infiltrating basophils in AD pathogenesis remains ill-defined. In this study, we aimed to clarify the role of basophils and their effector molecules triggering skin inflammation in oxazolone (OX)-induced murine model of AD.

Methods: A panel of mouse strains were sensitized and repeatedly challenged with topical applications of OX to induce AD-like skin inflammation. Both local and systemic Th2 immune responses were analyzed.

Results: Basophils progressively accumulated in the skin lesion but barely in draining lymph nodes (LNs). When basophils were depleted during the elicitation phase, skin inflammation was ameliorated while Th2 cell differentiation in draining LNs remained intact. The expression of IL-4 was highly upregulated in the affected skin, and basophils turned out to be the major producers of IL-4 among cellular infiltrates, suggesting the involvement of basophil-derived IL-4 in the Th2 skin inflammation. Indeed, basophil-specific IL-4-deficient mice displayed attenuated skin inflammation with a marked reduction of IL-4 in the skin lesion, even though cutaneous basophil infiltration and serum levels of IgE remained intact.

Conclusions: Skin-infiltrating basophils promoted OX-induced AD-like skin inflammation through their local production of IL-4, rather than the induction of Th2 cell differentiation in draining LNs. This study suggests that the selective targeting of basophils could be a beneficial strategy in the treatment of a certain type of AD.
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http://dx.doi.org/10.1111/all.14362DOI Listing
October 2020

Tolerogenic properties of CD206+ macrophages appeared in the sublingual mucosa after repeated antigen-painting.

Int Immunol 2020 07;32(8):509-518

Department of Molecular Immunology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.

The sublingual mucosa (SLM) in the oral cavity is utilized as the site for sublingual immunotherapy to induce tolerance against allergens. We previously reported that CD206+ round-type macrophage-like cells were induced in the SLM after repeated antigen (e.g. cedar pollen or fluorescein isothiocyanate (FITC))-painting. In this study, we examined the phenotypic and functional properties of CD206+ cells induced by repeated FITC-painting on the SLM. CD206+ cells after the repeated FITC-painting possessed a macrophage-like CD11b+Ly6C+ F4/80+CD64+ phenotype and expressed TIM-4, which was expressed in tolerogenic tissue-resident macrophages, at a high level. SLM CD206+ cells preferentially expressed molecules related to endocytosis and homeostatic processes, including the novel B7 family of immune checkpoint molecules, as assessed by microarray analyses. SLM CD206+ cells showed preferential expression of M2-related genes such as Fizz1, Aldh1a1 and Aldh1a2 but not Ym-1 and Arginase-1. A CD206+ cell-rich status inhibited OVA-specific CD4+ T-cell responses but reciprocally enhanced the proportion of both IL-10+CD4+ cells and Foxp3+ regulatory T-cells in regional lymph nodes. Co-culture of CD206+ cells with dendritic cells (DCs) showed that IL-12 production was suppressed in DCs concurrent with the decline of the MHC class IIhiCD86+ population, which was restored by neutralization of IL-10. These results demonstrate SLM CD206+ cells show the feature of tolerogenic macrophages and down-regulate the antigen-presenting cell function of mature DCs resulting in the inhibition of CD4+ T-cell responses.
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http://dx.doi.org/10.1093/intimm/dxaa014DOI Listing
July 2020

Dual real-time in vivo monitoring system of the brain-gut axis.

Biochem Biophys Res Commun 2020 04 26;524(2):340-345. Epub 2020 Jan 26.

Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan. Electronic address:

The brain-gut axis which is an interaction between recognition and emotion and the gut sensory system for food and microbiota is important for health. However, there is no real-time monitoring system of the brain and the gut simultaneously so far. We attempted to establish a dual real-time monitoring system for the brain-gut axis by a combination of intravital Ca imaging of the gut and electroencephalogram. Using a conditional Yellow Cameleon 3.60 expression mouse line, we performed intravital imaging of the gut, electrophysiological recordings of the vagus nerve, and electroencephalogram recordings of the various cortical regions simultaneously upon capsaicin stimuli as a positive control. Upon capsaicin administration into the small intestinal lumen, a simultaneous response of Ca signal in the enteric nervous system and cortical local field potentials (LFPs) was successfully observed. Both of them responded immediately upon capsaicin stimuli. Capsaicin triggered a significant increase in the frequency of vagus nerve spikes and a significant decrease in the slow-wave power of cortical LFPs. Furthermore, capsaicin induced delayed and sustained Ca signal in intestinal epithelial cells and then suppressed intestinal motility. The dual real-time monitoring system of the brain and the gut enables to dissect the interaction between the brain and the gut over time with precision.
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http://dx.doi.org/10.1016/j.bbrc.2020.01.090DOI Listing
April 2020

Selective suppression of oral allergen-induced anaphylaxis by Allergin-1 on basophils in mice.

Int Immunol 2020 03;32(3):213-219

Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.

Mast cells (MCs) play a critical role in oral allergen-induced anaphylaxis. However, the contribution of basophils to the anaphylaxis remains unclear. The inhibitory immunoreceptor Allergin-1 is highly expressed on MCs and basophils and inhibits FcεRI-mediated signaling in MCs. Here, we show that Allergin-1-deficient (Milr1-/-) mice developed more severe hypothermia, a higher mortality rate and a greater incidence of diarrhea than did wild-type (WT) mice in an oral ovalbumin (OVA)-induced food allergy model. MC-deficient Mas-TRECK mice, which had been reconstituted with either WT or Milr1-/- bone marrow-derived cultured MCs, did not develop hypothermia in this food allergy model. On the other hand, depletion of basophils by injection of anti-CD200R3 antibody rescued Milr1-/- mice from lethal hypothermia but not from diarrhea. In vitro analyses demonstrated that Allergin-1 inhibits IgE-dependent activation of both human and mouse basophils. Thus, Allergin-1 on basophils selectively suppresses oral allergen-induced anaphylaxis.
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http://dx.doi.org/10.1093/intimm/dxz075DOI Listing
March 2020

Propolis induces Ca signaling in immune cells.

Biosci Microbiota Food Health 2019 24;38(4):141-149. Epub 2019 Aug 24.

Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.

Propolis possesses several immunological functions. We recently generated a conditional Ca biosensor yellow cameleon (YC3.60) transgenic mouse line and established a five-dimensional (5D) (x, y, z, time, and Ca signaling) system for intravital imaging of lymphoid tissues, including Peyer's patches (PPs). To assess the effects of propolis on immune cells, we analyzed Ca signaling and using CD11c-Cre/YC3.60 transgenic mice, in which CD11c dendritic cells (DCs) specifically express YC3.60. We found that propolis induced Ca signaling in DCs in the PPs. Intravital imaging of PPs also showed that an intraperitoneal injection of propolis augmented Ca signaling in CD11c cells, suggesting that propolis possesses immune-stimulating activity. Furthermore, CD11c cells in PPs in mice administrated propolis indicated an increase in Ca signaling. Our results indicate that propolis induces immunogenicity under physiological conditions.
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http://dx.doi.org/10.12938/bmfh.19-011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856514PMC
August 2019

IL-3 Triggers Chronic Rejection of Cardiac Allografts by Activation of Infiltrating Basophils.

J Immunol 2019 06 8;202(12):3514-3523. Epub 2019 May 8.

Department of Internal Medicine II - Nephrology, University Hospital Regensburg, 93053 Regensburg, Germany;

Chronic rejection is a major problem in transplantation medicine, largely resistant to therapy, and poorly understood. We have shown previously that basophil-derived IL-4 contributes to fibrosis and vasculopathy in a model of heart transplantation with depletion of CD4 T cells. However, it is unknown how basophils are activated in the allografts and whether they play a role when cyclosporin A (CsA) immunosuppression is applied. BALB/c donor hearts were heterotopically transplanted into fully MHC-mismatched C57BL/6 recipients and acute rejection was prevented by depletion of CD4 T cells or treatment with CsA. We found that IL-3 is significantly upregulated in chronically rejecting allografts and is the major activator of basophils in allografts. Using IL-3-deficient mice and depletion of basophils, we show that IL-3 contributes to allograft fibrosis and organ failure in a basophil-dependent manner. Also, in the model of chronic rejection involving CsA, IL-3 and basophils substantially contribute to organ remodeling, despite the almost complete suppression of IL-4 by CsA. In this study, basophil-derived IL-6 that is resistant to suppression by CsA, was largely responsible for allograft fibrosis and limited transplant survival. Our data show that IL-3 induces allograft fibrosis and chronic rejection of heart transplants, and exerts its profibrotic effects by activation of infiltrating basophils. Blockade of IL-3 or basophil-derived cytokines may provide new strategies to prevent or delay the development of chronic allograft rejection.
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http://dx.doi.org/10.4049/jimmunol.1801269DOI Listing
June 2019

The basophil-IL-4-mast cell axis is required for food allergy.

Allergy 2019 10 8;74(10):1992-1996. Epub 2019 Jul 8.

Laboratory for Allergic Disease, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

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http://dx.doi.org/10.1111/all.13834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803027PMC
October 2019

Pivotal role of STIM2, but not STIM1, in IL-4 production by IL-3-stimulated murine basophils.

Sci Signal 2019 04 9;12(576). Epub 2019 Apr 9.

Department of Immune Regulation, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.

Basophils have nonredundant roles in various immune responses that require Ca influx. Here, we examined the role of two Ca sensors, stromal interaction molecule 1 and 2 (STIM1 and STIM2), in basophil activation. We found that loss of STIM1, but not STIM2, impaired basophil IL-4 production after stimulation with immunoglobulin E (IgE)-containing immune complexes. In contrast, when basophils were stimulated with IL-3, loss of STIM2, but not STIM1, reduced basophil IL-4 production. This difference in STIM proteins was associated with distinct time courses of Ca influx and transcription of the gene that were elicited by each stimulus. Similarly, basophil-specific STIM1 expression was required for IgE-driven chronic allergic inflammation in vivo, whereas STIM2 was required for IL-4 production after combined IL-3 and IL-33 treatment in mice. These data indicate that STIM1 and STIM2 have differential roles in the production of IL-4, which are stimulus dependent. Furthermore, these results illustrate the vital role of STIM2 in basophils, which is often considered to be less important than STIM1.
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http://dx.doi.org/10.1126/scisignal.aav2060DOI Listing
April 2019

Amphiregulin from Basophils Amplifies Basophil-Mediated Chronic Skin Inflammation.

J Invest Dermatol 2019 08 13;139(8):1834-1837.e2. Epub 2019 Mar 13.

Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

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http://dx.doi.org/10.1016/j.jid.2019.02.023DOI Listing
August 2019

Basophil-derived tumor necrosis factor can enhance survival in a sepsis model in mice.

Nat Immunol 2019 02 21;20(2):129-140. Epub 2019 Jan 21.

Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.

Basophils are evolutionarily conserved in vertebrates, despite their small numbers and short life span, suggesting that they have beneficial roles in maintaining health. However, these roles are not fully defined. Here we demonstrate that basophil-deficient mice exhibit reduced bacterial clearance and increased morbidity and mortality in the cecal ligation and puncture (CLP) model of sepsis. Among the several proinflammatory mediators that we measured, tumor necrosis factor (TNF) was the only cytokine that was significantly reduced in basophil-deficient mice after CLP. In accordance with that observation, we found that mice with genetic ablation of Tnf in basophils exhibited reduced systemic concentrations of TNF during endotoxemia. Moreover, after CLP, mice whose basophils could not produce TNF, exhibited reduced neutrophil and macrophage TNF production and effector functions, reduced bacterial clearance, and increased mortality. Taken together, our results show that basophils can enhance the innate immune response to bacterial infection and help prevent sepsis.
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http://dx.doi.org/10.1038/s41590-018-0288-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352314PMC
February 2019

Crucial Role for Basophils in Acquired Protective Immunity to Tick Infestation.

Front Physiol 2018 7;9:1769. Epub 2018 Dec 7.

Department of Immune Regulation, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

Ticks are blood-sucking arthropods that can transmit various pathogenic organisms to host animals and humans, causing serious infectious diseases including Lyme disease. Tick feeding induces innate and acquired immune responses in host animals, depending on the combination of different species of animals and ticks. Acquired tick resistance (ATR) can diminish the chance of pathogen transmission from infected ticks to the host. Hence, the elucidation of cellular and molecular mechanism underlying ATR is important for the development of efficient anti-tick vaccines. In this review article, we briefly overview the history of studies on ATR and summarize recent findings, particularly focusing on the role for basophils in the manifestation of ATR. In several animal species, including cattle, guinea pigs, rabbits and mice, basophil accumulation is observed at the tick re-infestation site, even though the frequency of basophils among cellular infiltrates varies in different animal species, ranging from approximately 3% in mice to 70% in guinea pigs. Skin-resident, memory CD4 T cells contribute to the recruitment of basophils to the tick re-infestation site through production of IL-3 in mice. Depletion of basophils before the tick re-infestation abolishes ATR in guinea pigs infested with and mice infested with , demonstrating the crucial role of basophils in the manifestation of ATR. The activation of basophils via IgE and its receptor FcεRI is essential for ATR in mice. Histamine released from activated basophils functions as an important effector molecule in murine ATR, probably through promotion of epidermal hyperplasia which interferes with tick attachment or blood feeding in the skin. Accumulating evidence suggests the following scenario. The 1 tick infestation triggers the production of IgE against tick saliva antigens in the host, and blood-circulating basophils bind such IgE on the cell surface via FcεRI. In the 2 infestation, IgE-armed basophils are recruited to tick-feeding sites and stimulated by tick saliva antigens to release histamine that promotes epidermal hyperplasia, contributing to ATR. Further studies are needed to clarify whether this scenario in mice can be applied to ATR in other animal species and humans.
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http://dx.doi.org/10.3389/fphys.2018.01769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293010PMC
December 2018

Basophils trigger emphysema development in a murine model of COPD through IL-4-mediated generation of MMP-12-producing macrophages.

Proc Natl Acad Sci U S A 2018 12 3;115(51):13057-13062. Epub 2018 Dec 3.

Department of Immune Regulation, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan;

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. It has generally been considered a non-Th2-type lung disorder, characterized by progressive airflow limitation with inflammation and emphysema, but its cellular and molecular mechanism remains ill defined, compared with that of asthma characterized by reversible airway obstruction. Here we show a previously unappreciated role for basophils at the initiation phase of emphysema formation in an elastase-induced murine model of COPD in that basophils represent less than 1% of lung-infiltrating cells. Intranasal elastase instillation elicited the recruitment of monocytes to the lung, followed by differentiation into interstitial macrophages (IMs) but rarely alveolar macrophages (AMs). Matrix metalloproteinase-12 (MMP-12) contributing to emphysema formation was highly expressed by IMs rather than AMs, in contrast to the prevailing assumption. Experiments using a series of genetically engineered mice suggested that basophil-derived IL-4, a Th2 cytokine, acted on lung-infiltrating monocytes to promote their differentiation into MMP-12-producing IMs that resulted in the destruction of alveolar walls and led to emphysema development. Indeed, mice deficient for IL-4 only in basophils failed to generate pathogenic MMP-12-producing IMs and hence develop emphysema. Thus, the basophil-derived IL-4/monocyte-derived IM/MMP-12 axis plays a crucial role in emphysema formation and therefore may be a potential target to slow down emphysema progression at the initiation phase of COPD.
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http://dx.doi.org/10.1073/pnas.1813927115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305004PMC
December 2018

Aggregation makes a protein allergenic at the challenge phase of basophil-mediated allergy in mice.

Int Immunol 2019 02;31(1):41-49

Department of Immune Regulation, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan.

A hapten is a small molecule that is not immunogenic on its own but can stimulate the production of antibodies at the sensitization phase when conjugated to carrier proteins. The hapten then reacts specifically with the antibodies generated against it to elicit an immune or allergic response at the challenge phase. Here, we compared various carrier proteins conjugated with the same hapten in their ability to induce hapten-specific IgE-mediated allergic responses in vitro and in vivo, and characterized the nature of carrier proteins that determines the magnitude of response at the challenge phase of allergic reactions. Hapten 2,4,6-trinitrophenol (TNP)-conjugated ovalbumin (TNP-OVA) and bovine serum albumin (TNP-BSA) elicited TNP-specific, mast cell-dependent, immediate-type allergic reactions at a comparable level in mice that had been passively sensitized with TNP-specific IgE. In contrast, TNP-OVA but not TNP-BSA efficiently induced a basophil-dependent, IgE-mediated chronic allergic inflammation (IgE-CAI), even though both proteins could stimulate basophils in vitro at a comparable level. By comparing different carrier proteins and structurally modifying them, we found that the formation of large aggregates is crucial for TNP-conjugated carrier proteins to efficiently elicit IgE-CAI, regardless of the type of protein. Thus, the aggregation status of carrier proteins appears to determine the magnitude of allergic response at the challenge phase of hapten-specific IgE-CAI. Our findings suggest that the allergenicity of substances is a matter of importance not only at the sensitization but also at the challenge phase in a certain type of allergy including a basophil-mediated allergic inflammation.
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http://dx.doi.org/10.1093/intimm/dxy062DOI Listing
February 2019

How do basophils contribute to Th2 cell differentiation and allergic responses?

Int Immunol 2018 08;30(9):391-396

Department of Immune Regulation, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan.

Basophils and mast cells share some features, including basophilic granules in the cytoplasm, cell surface expression of the high-affinity IgE receptor and release of chemical mediators such as histamine. Because of this similarity and their minority status, basophils had often been erroneously considered as minor relatives or blood-circulating precursors of tissue-resident mast cells, and therefore long been neglected or underestimated in immunological studies. Taking advantage of newly developed tools, such as basophil-depleting antibodies and engineered mice deficient for only basophils, recent studies have identified previously unappreciated roles for basophils, distinct from those played by mast cells, in allergic responses, protective immunity against parasitic infections and regulation of other immune cells. In this review, we focus on two topics that we presented and discussed in the 46th Annual Meeting of the Japanese Society for Immunology held in Sendai in December 2017. The first topic is the function of basophils as antigen-presenting cells for driving Th2 cell differentiation. We demonstrated that basophils produce few or no MHC class II (MHC-II) proteins by themselves although they can acquire peptide-MHC-II complexes from dendritic cells through trogocytosis, and present them and provide IL-4 to naive CD4 T cells, promoting Th2 cell differentiation. The second topic is the basophil-specific effector molecules involved in allergic responses. Among mouse mast cell proteases (mMCPs), mMCP-8 and mMCP-11 are expressed almost exclusively by basophils. Analyses in vitro and in vivo revealed that both proteases can induce leukocyte migration through distinct mechanisms, contributing to the development of basophil-dependent allergic inflammation.
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http://dx.doi.org/10.1093/intimm/dxy026DOI Listing
August 2018

Histamine Released From Skin-Infiltrating Basophils but Not Mast Cells Is Crucial for Acquired Tick Resistance in Mice.

Front Immunol 2018 3;9:1540. Epub 2018 Jul 3.

Department of Immune Regulation, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

Ticks are blood-feeding arthropods that can transmit pathogens to humans and animals, leading to serious infectious diseases such as Lyme disease. After single or multiple tick infestation, some animal species develop resistance to tick feeding, leading to reduced risk of pathogen transmission. In mice infested with larval ticks, both mast cells and basophils reportedly play key roles in the manifestation of acquired tick resistance (ATR), but it remains ill-defined how they contribute to it. Here, we investigated their products responsible for ATR. Treatment of mice with antihistamine abolished the ATR while histamine or histamine H1 receptor agonist reduced tick-feeding even in the first infestation. In accordance with these, mice deficient for histamine production showed little or no ATR, indicating the crucial role for histamine in the expression of ATR. Adoptive transfer of mast cells and basophils derived from histamine-sufficient or deficient mice to recipient mice lacking mast cells and basophils, respectively, revealed that histamine produced by basophils but not mast cells is essential for the manifestation of ATR, in contrast to the case of local and systemic anaphylaxis where mast cell-derived histamine is the major player. During the second but not first tick infestation, basophils accumulated and made a cluster, surrounding a tick mouthpart, in the epidermis whereas mast cells were scattered and localized mainly in the dermis, more distantly from a tick mouthpart. This appears to explain why basophil-derived histamine is much more effective than mast cell-derived one. Histamine-sufficient, but not -deficient mice showed the thickened epidermis at the second tick-feeding site. Taken together, histamine released from skin-infiltrating basophils rather than skin-resident mast cells plays a crucial role in the manifestation of ATR, perhaps through promotion of epidermal hyperplasia that may inhibit tick feeding.
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http://dx.doi.org/10.3389/fimmu.2018.01540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043789PMC
July 2018

Stable lines and clones of long-term proliferating normal, genetically unmodified murine common lymphoid progenitors.

Blood 2018 05 23;131(18):2026-2035. Epub 2018 Mar 23.

Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Germany.

Common lymphoid progenitors (CLPs) differentiate to T and B lymphocytes, dendritic cells, natural killer cells, and innate lymphoid cells. Here, we describe culture conditions that, for the first time, allow the establishment of lymphoid-restricted, but uncommitted, long-term proliferating CLP cell lines and clones from a small pool of these cells from normal mouse bone marrow, without any genetic manipulation. Cells from more than half of the cultured CLP clones could be induced to differentiate to T, B, natural killer, dendritic, and myeloid cells in vitro. Cultured, transplanted CLPs transiently populate the host and differentiate to all lymphoid subsets, and to myeloid cells in vivo. This simple method to obtain robust numbers of cultured noncommitted CLPs will allow studies of cell-intrinsic and environmentally controlled lymphoid differentiation programs. If this method can be applied to human CLPs, it will provide new opportunities for cell therapy of patients in need of myeloid-lymphoid reconstitution.
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http://dx.doi.org/10.1182/blood-2017-09-805259DOI Listing
May 2018

Prostaglandin D amplifies lupus disease through basophil accumulation in lymphoid organs.

Nat Commun 2018 02 20;9(1):725. Epub 2018 Feb 20.

Centre de Recherche sur l'Inflammation, INSERM UMR1149, CNRS ERL8252, Sorbonne Paris Cité, Faculté de Médecine site Bichat, Laboratoire d'Excellence Inflamex, DHU FIRE, Université Paris Diderot, 16 rue Henri Huchard, 75018, Paris, France.

In systemic lupus erythematosus (SLE), autoantibody production can lead to kidney damage and failure, known as lupus nephritis. Basophils amplify the synthesis of autoantibodies by accumulating in secondary lymphoid organs. Here, we show a role for prostaglandin D (PGD) in the pathophysiology of SLE. Patients with SLE have increased expression of PGD receptors (PTGDR) on blood basophils and increased concentration of PGD metabolites in plasma. Through an autocrine mechanism dependent on both PTGDRs, PGD induces the externalization of CXCR4 on basophils, both in humans and mice, driving accumulation in secondary lymphoid organs. Although PGD can accelerate basophil-dependent disease, antagonizing PTGDRs in mice reduces lupus-like disease in spontaneous and induced mouse models. Our study identifies the PGD/PTGDR axis as a ready-to-use therapeutic modality in SLE.
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http://dx.doi.org/10.1038/s41467-018-03129-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5820278PMC
February 2018

B cell activation in the cecal patches during the development of an experimental colitis model.

Biochem Biophys Res Commun 2018 02 10;496(2):367-373. Epub 2018 Jan 10.

Department of Gastroenterology, Graduate School of Medical Science, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. Electronic address:

Although previous studies have suggested that appendix seems to be involved in the colitis, the role of this in the pathogenesis remains unclear. In this study, we assessed the importance of appendiceal lymphoid follicles, specifically the cecal patches (CP) in mice, using an experimental colitis model. Treatment with oxazolone resulted in ulcerations particularly at CP with follicular expansion as well as colitis. The colitis was attenuated by either appendectomy or the absence of mature B cells. We therefore established an intravital imaging system accompanied by the fluorescence resonance energy transfer technology to analyze the dynamic immune response of CP B cells. Our observation revealed frequent Ca signaling in CP B cells during the early phase of colitis development. These findings suggested that the CP B cells may be involved in the pathogenesis of colitis including inflammatory bowel diseases in humans.
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http://dx.doi.org/10.1016/j.bbrc.2018.01.053DOI Listing
February 2018

Multifaceted roles of basophils in health and disease.

J Allergy Clin Immunol 2018 08 14;142(2):370-380. Epub 2017 Dec 14.

Department of Immune Regulation, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

Until recently, basophils had often been neglected in immunologic studies because of their minority status among immune cells or confused with tissue-resident mast cells because of some phenotypic similarities between them in spite of different anatomic localization. It is now appreciated that basophils and mast cells are distinct cell lineages and that basophils play important and nonredundant roles distinct from those played by mast cells. On the one hand, basophils contribute beneficially to protective immunity, particularly against parasitic infections. On the other hand, basophils are involved in the development of various disorders, including allergy and autoimmune disease. Basophils interact with other immune cells and nonhematopoietic cells through cell-to-cell contact or basophil-derived factors, such as cytokines and proteases, contributing to the regulation of immune and allergic responses. In this review article we highlight recent advances in our understanding of basophil pathophysiology in human subjects and animal models by consolidating research findings reported during the past 5 years. Further studies on basophils and their products will help identify suitable targets for novel therapeutics in allergy and effective vaccines against parasitic infection.
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http://dx.doi.org/10.1016/j.jaci.2017.10.042DOI Listing
August 2018

Skin CD4 Memory T Cells Play an Essential Role in Acquired Anti-Tick Immunity through Interleukin-3-Mediated Basophil Recruitment to Tick-Feeding Sites.

Front Immunol 2017 16;8:1348. Epub 2017 Oct 16.

Department of Immune Regulation, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

Ticks, blood-sucking arthropods, serve as vectors for transmission of infectious diseases including Lyme borreliosis. After tick infestation, several animal species can develop resistance to subsequent infestations, reducing the risk of transmission. In a mouse model, basophils reportedly infiltrate tick-feeding sites during the second but not first infestation and play a crucial role in the expression of acquired tick resistance. However, the mechanism underlying basophil recruitment to the second tick-feeding site remains ill-defined. Here, we investigated cells and their products responsible for the basophil recruitment. Little or no basophil infiltration was detected in T-cell-deficient mice, and adoptive transfer of CD4 but not CD8 T cells reconstituted it. gene expression was highly upregulated at the second tick-feeding site, and adoptive transfer of interleukin-3 (IL-3)-sufficient but not IL-3-deficient CD4 T cells conferred the basophil infiltration on T-cell-deficient mice, indicating that the CD4 T-cell-derived IL-3 is essential for the basophil recruitment. Notably, IL-3 resident CD4 memory T cells were detected even before the second infestation in previously uninfested skin distant from the first tick-feeding site. Taken together, IL-3 produced locally by skin CD4 memory T cells appears to play a crucial role in basophil recruitment to the second tick-feeding site.
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http://dx.doi.org/10.3389/fimmu.2017.01348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650685PMC
October 2017

Differential usage of COX-1 and COX-2 in prostaglandin production by mast cells and basophils.

Biochem Biophys Rep 2017 Jul 15;10:82-87. Epub 2017 Mar 15.

Department of Immune Regulation, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.

Basophils have been erroneously considered as minor relatives of mast cells, due to some phenotypic similarity between them. While recent studies have revealed non-redundant roles for basophils in various immune responses, basophil-derived effector molecules, including lipid mediators, remain poorly characterized, compared to mast cell-derived ones. Here we analyzed and compared eicosanoids produced by mouse basophils and mast cells when stimulated with IgE plus allergens. The production of 5-LOX metabolites such as LTB4 and 5-HETE was detected as early as 0.5 h post-stimulation in both cell types, even though their amounts were much smaller in basophils than in mast cells. In contrast, basophils and mast cells showed distinct time course in the production of COX metabolites, including PGD2, PGE2 and 11-HETE. Their production by mast cells was detected at both 0.5 and 6 h post-stimulation while that by basophils was detectable only at 6 h. Of note, mast cells showed 8-9 times higher levels of COX-1 than did basophils at the resting status. In contrast to unaltered COX-1 expression with or without stimulation, COX-2 expression was up-regulated in both cell types upon activation. Importantly, when activated, basophils expressed 4-5 times higher levels of COX-2 than did mast cells. In accordance with these findings, the late-phase production of the COX metabolites by basophils was completely ablated by COX-2 inhibitor whereas the early-phase production by mast cells was blocked by COX-1 but not COX-2 inhibitor. Thus, the production of COX metabolites is differentially regulated by COX-1 and COX-2 in basophils and mast cells.
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http://dx.doi.org/10.1016/j.bbrep.2017.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5614629PMC
July 2017

Basophils contribute to pristane-induced Lupus-like nephritis model.

Sci Rep 2017 08 11;7(1):7969. Epub 2017 Aug 11.

Centre de Recherche sur l'Inflammation, INSERM UMR1149, CNRS ERL8252, Université Paris Diderot, Sorbonne Paris Cité, Faculté de Médecine site Bichat, Laboratoire d'Excellence Inflamex, DHU FIRE, Paris, France.

Lupus nephritis (LN), one of the most severe outcomes of systemic lupus erythematosus (SLE), is initiated by glomerular deposition of immune-complexes leading to an inflammatory response and kidney failure. Autoantibodies to nuclear antigens and autoreactive B and T cells are central in SLE pathogenesis. Immune mechanisms amplifying this autoantibody production drive flares of the disease. We previously showed that basophils were contributing to LN development in a spontaneous lupus-like mouse model (constitutive Lyn mice) and in SLE subjects through their activation and migration to secondary lymphoid organs (SLOs) where they amplify autoantibody production. In order to study the basophil-specific mechanisms by which these cells contribute to LN development, we needed to validate their involvement in a genetically independent SLE-like mouse model. Pristane, when injected to non-lupus-prone mouse strains, induces a LN-like disease. In this inducible model, basophils were activated and accumulated in SLOs to promote autoantibody production. Basophil depletion by two distinct approaches dampened LN-like disease, demonstrating their contribution to the pristane-induced LN model. These results enable further studies to decipher molecular mechanisms by which basophils contribute to lupus progression.
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http://dx.doi.org/10.1038/s41598-017-08516-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5554199PMC
August 2017

Recent advances in understanding basophil-mediated Th2 immune responses.

Immunol Rev 2017 07;278(1):237-245

Department of Immune Regulation, Tokyo Medical and Dental University (TMDU), Graduate School of Medical and Dental Sciences, Tokyo, Japan.

Basophils, the least common granulocytes, represent only ~0.5% of peripheral blood leukocytes. Because of the small number and some similarity with mast cells, the functional significance of basophils remained questionable for a long time. Recent studies using newly-developed analytical tools have revealed crucial and non-redundant roles for basophils in various immune responses, particularly Th2 immunity including allergy and protective immunity against parasitic infections. In this review, we discuss the mechanisms how basophils mediate Th2 immune responses and the nature of basophil-derived factors involved in them. Activated basophils release serine proteases, mouse mast cell protease 8 (mMCP-8), and mMCP-11, that are preferentially expressed by basophils rather than mast cells in spite of their names. These proteases elicit microvascular hyperpermeability and leukocyte infiltration in affected tissues, leading to inflammation. Basophil-derived IL-4 also contributes to eosinophil infiltration while it acts on tissue-infiltrating inflammatory monocytes to promote their differentiation into M2 macrophages that in turn dampen inflammation. Although basophils produce little or no MHC class II (MHC-II) proteins, they can acquire peptide-MHC-II complexes from dendritic cells via trogocytosis and present them together with IL-4 to naive CD4 T cells, leading to Th2 cell differentiation. Thus, basophils contribute to Th2 immunity at various levels.
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http://dx.doi.org/10.1111/imr.12548DOI Listing
July 2017

Emerging roles of basophils in allergic inflammation.

Allergol Int 2017 Jul 11;66(3):382-391. Epub 2017 May 11.

Department of Immune Regulation, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

Basophils have long been neglected in immunological studies because they were regarded as only minor relatives of mast cells. However, recent advances in analytical tools for basophils have clarified the non-redundant roles of basophils in allergic inflammation. Basophils play crucial roles in both IgE-dependent and -independent allergic inflammation, through their migration to the site of inflammation and secretion of various mediators, including cytokines, chemokines, and proteases. Basophils are known to produce large amounts of IL-4 in response to various stimuli. Basophil-derived IL-4 has recently been shown to play versatile roles in allergic inflammation by acting on various cell types, including macrophages, innate lymphoid cells, fibroblasts, and endothelial cells. Basophil-derived serine proteases are also crucial for the aggravation of allergic inflammation. Moreover, recent reports suggest the roles of basophils in modulating adaptive immune responses, particularly in the induction of Th2 differentiation and enhancement of humoral memory responses. In this review, we will discuss recent advances in understanding the roles of basophils in allergic inflammation.
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http://dx.doi.org/10.1016/j.alit.2017.04.007DOI Listing
July 2017