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Pulmonary arterial hypertension (PAH) is characterized by the severe obstruction of the small pulmonary arteries and concomitant high pulmonary arterial pressure, resulting in progressive right ventricular failure. Previously, we demonstrated that long-term interleukin (IL)-33 administration in mice induces severe occlusive medial hypertrophy of pulmonary arteries (PA) in the lungs, which is mediated by group 2 innate lymphoid cells (ILC2s). In response to IL-33, ILC2s accumulate around the blood vessels and produce IL-5, leading to perivascular eosinophil recruitment. In this study, we characterized IL-33-induced medial hypertrophy of PA. We demonstrated that long-term IL-33 administration causes an increase in right ventricular pressure. In IL-33-deficient mice, medial hypertrophy of PA mediated by eggs of Schistosoma mansoni was attenuated, accompanied by a partial reduction in ILC2s, eosinophils, and CD4 + T cells. In addition, proteomic analysis revealed dramatic changes in the urine samples from mice treated with IL-33 or S. mansoni eggs. Resistin-like alpha (RELMα), a pulmonary hypertension-related molecule, was commonly detected in the urine in both treatments. Large amounts of RELMα were observed in the lungs of the IL-33-treated mice. These observations suggest that IL-33-induced medial hypertrophy of PA is a useful model for studying the mechanism underlying the development of PAH and finding biomarkers to indicate the onset of PAH., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Masashi Ikutani reports financial support was provided by Hiroshima University. Shoichi Shimizu reports financial support was provided by University of Occupational and Environmental Health, Japan. Koki Okada reports financial support was provided by Hiroshima University. Koshi Imami reports financial support was provided by RIKEN. Tadakatsu Inagaki reports financial support was provided by National Cerebral and Cardiovascular Center Research Institute. Yoshikazu Nakaoka reports financial support was provided by National Cerebral and Cardiovascular Center Research Institute. Yoshio Osada reports financial support was provided by University of Occupational and Environmental Health, Japan. Susumu Nakae reports financial support was provided by Hiroshima University., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Severely immunodeficient mice are useful for understanding the pathogenesis of certain tumors and for developing therapeutic agents for such tumors. In addition, engraftment of these mice with human hematopoietic cells can yield information that helps us understand the in vivo molecular mechanisms underlying actual human viral infections. In our present research, we discovered a novel, severely immunodeficient strain of mice having a mutation in exon 57 of the Prkdc gene (Prkdc Δex57/Δex57 ) in an inbred colony of B10.S/SgSlc mice. Those Prkdc Δex57/Δex57 mice showed thymic hypoplasia and lack of mature T cells and B cells in peripheral lymphoid tissues, resulting in very low levels of production of serum immunoglobulins. In addition, those mice were highly susceptible to influenza viruses due to the lack of acquired immune cells. On the other hand, since they had sufficient numbers of NK cells, they rejected tumor transplants, similarly to Prkdc +/+ mice. Next, we generated Foxn1 nu/nu Prkdc Δex57/Δex57 Il2rg -/- (NPG) mice on the BALB/cSlc background, which lack all lymphocytes such as T cells, B cells and innate lymphoid cells, including NK cells. As expected, these mice were able to undergo engraftment of human tumor cell lines. These findings suggest that Prkdc Δex57/Δex57 mice will be useful as a novel model of immunodeficiency, while NPG mice will be useful for xenografting of various malignancies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Yumie Takagi reports financial support was provided by Japan SLC, Inc.Katsuko Sudo reports financial support was provided by Tokyo Medical University.Sachiko Yamaguchi, Masashi Ikutani and Susumu Nakae report financial support was provided by Hiroshima University.Shuzo Urata and Jiro Yasuda report financial support was provided by Nagasaki University.Tatsukuni Ohno reports financial support was provided by Tokyo Dental College.Sachiko Hirose reports financial support was provided by Toin University.Kiyoshi Matsumoto reports financial support was provided by Shinshu University.Takeshi Kuramoto reports financial support was provided by Tokyo University of Agriculture.Tadao Serikawa reports financial support was provided by Kyoto University., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by type 2 immune responses. Interleukin-25 (IL-25) is produced predominantly by epithelial cells. It can activate Th2 cells to produce type 2 cytokines such as IL-4, IL-5 and IL-13, contributing to host defense against nematodes. However, excessive/inappropriate production of IL-25 is considered to be involved in development of type 2 cytokine-associated allergic disorders such as asthma. On the other hand, the contribution of IL-25 to the pathogenesis of AD remains poorly understood. In the present study, we found that expression of Il25 mRNA was significantly increased in the skin of mice during oxazolone-induced chronic contact hypersensitivity (CHS), which is a mouse model of human AD. In addition, development of oxazolone-induced chronic CHS was significantly reduced in IL-25-deficient (Il25 -/- ) mice compared with wild-type mice on the C57BL/6, but not BALB/c, background, although IL-25 was not essential for IL-4 production by hapten-specific T cells. Therefore, IL-25 is crucial for development of chronic CHS, although that is partly dependent on the genetic background of the mice., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Susumu Nakae reports financial support was provided by Hiroshima University. Eri Shimura reports financial support was provided by Juntendo University. Hajime Suto reports financial support was provided by Juntendo University. Takafumi Numata reports financial support was provided by Tokyo Medical University. Sachiko Yamaguchi reports financial support was provided by Hiroshima University. Kazutoshi Harada reports financial support was provided by Tokyo Medical University. Ko Okumura reports financial support was provided by Juntendo University. Katsuko Sudo reports financial support was provided by Tokyo Medical University. Masashi Ikutani reports financial support was provided by Hiroshima University., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Interleukin (IL)-5 is a critical regulator of eosinophils and a therapeutic target for asthma. The administration of anti-IL-5 or anti-IL-5 receptor (IL-5R) antibodies has been shown to reduce eosinophil counts and ameliorate asthmatic symptoms in studies on animal models of allergy as well as in human clinical trials. In order to explore other potential clinical uses of IL-5R antibodies, we used an animal model of IL-33-mediated pulmonary arterial hypertrophy. We first generated chimeric monoclonal antibodies against the mouse IL-5 receptor α chain (IL-5Rα), which comprised an Fc region from human IgG1 and a Fab region from a previously established anti-mouse IL-5Rα monoclonal antibody. To investigate the role of antibody-dependent cell-mediated cytotoxicity (ADCC), chimeric antibodies that lacked ADCC were prepared. These antibodies recognized IL-5Rα to the same extent as the ADCC-sufficient antibodies. Administration of chimeric antibodies with ADCC resulted in the elimination of eosinophils from the lung and thus suppressed the development of arterial hypertrophy. This effect was attenuated in mice treated with antibodies lacking ADCC. Taken together, the results of this study provided a potential use for anti-IL-5Rα antibodies in the treatment of arterial hypertrophy, which leads to pulmonary hypertension., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Cyclosporin A (CsA) is a well-known immunosuppressant that is used against steroid-resistant asthma. Group 2 innate lymphoid cells (ILC2s) and type 2 helper T (Th2) cells produce Th2 cytokines including IL-5 and play important roles in asthma pathogenesis. Here, we studied the effects of CsA in allergen-induced lung inflammation in mice and found that CsA decreased the number of lung ILC2s and attenuated papain-induced activation of ILC2s accompanied with IL-5 expression. The ILC2 suppression mediated by CsA was not observed in culture or in lymphocyte-deficient Rag2 -/- mice. Thus, we propose a new suppressive effect of CsA, i.e., administration of CsA indirectly suppresses maintenance and activation of lung ILC2s in addition to direct suppression of T-cell activation and cytokine production., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Syntenin-1 is an intracellular PDZ protein that binds multiple proteins and regulates protein trafficking, cancer metastasis, exosome production, synaptic formation, and IL-5 signaling. However, the functions of Syntenin-1 have not yet been clearly characterized in detail, especially in vivo. In this study, we generated a Syntenin-1 knock out (KO) mouse strain and analyzed the role(s) of Syntenin-1 in IL-5 signaling, because the direct interaction of Syntenin-1 with the cytoplasmic domain of the IL-5 receptor α subunit and the regulation of IL-5 signaling by Syntenin-1 have been reported. Unexpectedly, the number of IL-5-responding cells was normal and the levels of fecal immunoglobulins were rather higher in the Syntenin-1 KO mice. We also found that IgA and IgM production of splenic B cells stimulated in vitro was increased in Syntenin-1 KO mice. In addition, we showed that a distribution of intestinal microbial flora was influenced in Syntenin-1 KO mice. Our data indicate that Syntenin-1 negatively regulates the intestinal immunoglobulin production and has a function to maintain the intestinal homeostasis in vivo. The analysis of Syntenin-1 KO mice may provide novel information on not only mucosal immunity but also other functions of Syntenin-1 such as cancer metastasis and neural development., (Copyright © 2014 The Authors. Published by Elsevier GmbH.. All rights reserved.)