Publications by authors named "Masayuki Nishide"

28 Publications

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IL-33 Induces Sema4A Expression in Dendritic Cells and Exerts Antitumor Immunity.

J Immunol 2021 09 11;207(5):1456-1467. Epub 2021 Aug 11.

Laboratory of Immunopathology, Immunology Frontier Research Center, World Premier International Research Center, Osaka University, Suita, Osaka, Japan;

Cancer immunotherapy has shown great promise as a new standard therapeutic strategy against cancer. However, the response rate and survival benefit remain unsatisfactory because most current approaches, such as the use of immune checkpoint inhibitors, depend on spontaneous antitumor immune responses. One possibility for improving the efficacy of immunotherapy is to promote antitumor immunity using adjuvants or specific cytokines actively. IL-33 has been a candidate for such cytokine therapies, but it remains unclear how and in which situations IL-33 exerts antitumor immune effects. In this study, we demonstrate the potent antitumor effects of IL-33 using syngeneic mouse models, which included marked inhibition of tumor growth and upregulation of IFN-γ production by tumor-infiltrating CD8 T cells. Of note, IL-33 induced dendritic cells to express semaphorin 4A (Sema4A), and the absence of Sema4A abolished the antitumor activity of IL-33, indicating that Sema4A is intrinsically required for the antitumor effects of IL-33 in mice. Collectively, these results not only present IL-33 and Sema4A as potential therapeutic targets but also shed light on the potential use of Sema4A as a biomarker for dendritic cell activation status, which has great value in various fields of cancer research, including vaccine development.
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http://dx.doi.org/10.4049/jimmunol.2100076DOI Listing
September 2021

The lysosomal Ragulator complex plays an essential role in leukocyte trafficking by activating myosin II.

Nat Commun 2021 06 7;12(1):3333. Epub 2021 Jun 7.

Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

Lysosomes are involved in nutrient sensing via the mechanistic target of rapamycin complex 1 (mTORC1). mTORC1 is tethered to lysosomes by the Ragulator complex, a heteropentamer in which Lamtor1 wraps around Lamtor2-5. Although the Ragulator complex is required for cell migration, the mechanisms by which it participates in cell motility remain unknown. Here, we show that lysosomes move to the uropod in motile cells, providing the platform where Lamtor1 interacts with the myosin phosphatase Rho-interacting protein (MPRIP) independently of mTORC1 and interferes with the interaction between MPRIP and MYPT1, a subunit of myosin light chain phosphatase (MLCP), thereby increasing myosin II-mediated actomyosin contraction. Additionally, formation of the complete Ragulator complex is required for leukocyte migration and pathophysiological immune responses. Together, our findings demonstrate that the lysosomal Ragulator complex plays an essential role in leukocyte migration by activating myosin II through interacting with MPRIP.
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http://dx.doi.org/10.1038/s41467-021-23654-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184920PMC
June 2021

Pulmonary artery hypertension prior to the relapse of adult-onset Still's disease.

Respirol Case Rep 2021 May 28;9(5):e00746. Epub 2021 Apr 28.

Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine Osaka University Osaka Japan.

Adult-onset Still's disease (AOSD) is a rare inflammatory autoimmune disorder characterized by fever, skin rash, and arthralgia. Pulmonary artery hypertension (PAH) rarely occurs with AOSD and has not been reported in the absence of typical symptoms of AOSD. A 33-year-old woman was admitted to our hospital with dyspnoea on exertion. Although she had not had symptoms of AOSD for 18 months before her admission, she presented with gradually progressing PAH. Because she had no typical symptoms of AOSD, she was treated with pulmonary vasodilators. However, her PAH did not improve. At one month after vasodilator treatment, she developed a high fever with elevation of ferritin. We determined that her AOSD had relapsed. Immunosuppressants were started and both her AOSD and PAH quickly improved. PAH may develop in the absence of typical symptoms of AOSD and immunosuppressants may be effective in such a case.
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http://dx.doi.org/10.1002/rcr2.746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080289PMC
May 2021

Extended single-dose toxicity study of [At]NaAt in mice for the first-in-human clinical trial of targeted alpha therapy for differentiated thyroid cancer.

Ann Nucl Med 2021 Jun 19;35(6):702-718. Epub 2021 Apr 19.

Institute for Radiation Sciences, Osaka University, Suita, Japan.

Objective: Astatine (At) is a promising alpha emitter as an alternative to iodine (I). We are preparing the first-in-human (FIH) clinical trial of targeted alpha therapy for differentiated thyroid cancer in consultation with Pharmaceuticals and Medical Devices Agency. Here, we performed an extended single-dose toxicity examination under a reliability standard, as a preclinical safety assessment of [At]NaAt to determine the FIH dose.

Methods: [At]NaAt solution was injected into normal 6-week-old mice (male (n = 50) and female (n = 50), body weight: male 33.2 ± 1.7 g, female 27.3 ± 1.5 g), which were then divided into four groups: 5 MBq/kg (n = 20), 20 MBq/kg (n = 20), 50 MBq/kg (n = 30), saline control (n = 30). The mice were followed up for 5 days (primary evaluation point for acute toxicity: n = 80) or 14 days (n = 20: evaluation point for recovery) to monitor general condition and body weight change. At the end of the observation period, necropsy, blood test, organ weight measurement, and histopathological examination were performed. For body weight, blood test, and organ weight, statistical analyses were performed to compare data between the control and injected groups.

Results: No abnormal findings were observed in the general condition of mice. In the 50 MBq/kg group, males (days 3 and 5) showed a significant decrease in body weight compared with the control. However, necropsy did not differ significantly beyond the range of spontaneous lesions. In the blood test, males (50 MBq/kg) and females (50 MBq/kg) showed a decrease in white blood cell and platelet counts on day 5, and recovery on day 14. In the testis, a considerable weight decrease was observed on day 14 (50 MBq/kg), and multinucleated giant cells were observed in all mice, indicating a significant change related to the administration of [At]NaAt.

Conclusions: In the extended single-dose toxicity study of [At]NaAt, administration of high doses resulted in weight loss, transient bone marrow suppression, and pathological changes in the testis, which require consideration in the FIH clinical trial.
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http://dx.doi.org/10.1007/s12149-021-01612-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134311PMC
June 2021

Recovery from prolonged thrombocytopenia in patients with TAFRO syndrome: case series and literature review.

Mod Rheumatol Case Rep 2020 07 3;4(2):302-309. Epub 2020 Feb 3.

Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.

TAFRO syndrome is a newly proposed disease that is characterised by thrombocytopenia, anasarca, fever, reticulin fibrosis (or renal dysfunction), and organomegaly. Generally, high doses of corticosteroids are recommended for the initial treatment of TAFRO syndrome; however, some patients experience prolonged refractory thrombocytopenia after initiating such therapies. If corticosteroid treatment alone is ineffective, additional immunosuppressive therapies such as cyclosporine A are recommended. Since long-term use of immunosuppressive therapies with TAFRO syndrome sometimes causes serious infection, it is important to recognise the time to recovery from thrombocytopenia. In this study, we investigated how long it took to recover from thrombocytopenia, to aid clinicians in decision-making regarding the need to strengthen treatment for prolonged thrombocytopenia. Here, we describe three of our patients with TAFRO syndrome exhibiting prolonged thrombocytopenia. We also investigated the median period to recovery from this complication (defined as the time to increase the platelet count above 50,000/µL) after the initiation of high-dose corticosteroid treatment in our 3 cases and 38 peer-reviewed cases. We found that it took our patients 61 days to recover from thrombocytopenia; in comparison, our investigation of the 38 peer-reviewed case reports revealed a median recovery time of 47.5 days among previously reported patients. We showed the time to recovery from thrombocytopenia in patients with TAFRO syndrome for the first time. Our findings ought to be useful for decision-making among clinicians regarding the administration of other immunosuppressive treatments in addition to corticosteroid.
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http://dx.doi.org/10.1080/24725625.2020.1717747DOI Listing
July 2020

Pathological and therapeutic implications of eosinophil-derived semaphorin 4D in eosinophilic chronic rhinosinusitis.

J Allergy Clin Immunol 2020 03 5;145(3):843-854.e4. Epub 2020 Feb 5.

Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan; Laboratory of Immunopathology, World Premier International Immunology Frontier Research Center, Suita City, Osaka, Japan; Institute for Open and Transdisciplinary Research Initiatives, Suita City, Osaka, Japan. Electronic address:

Background: Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis. Clinical markers for ECRS disease activity and treatment strategies have not been sufficiently established. Although semaphorins are originally identified as neuronal guidance factors, it is becoming clear that they play key roles in immune regulation and inflammatory diseases.

Objective: We sought to investigate the pathological functions and therapeutic potential of semaphorin 4D (SEMA4D) in ECRS.

Methods: Serum soluble SEMA4D levels in patients with paranasal sinus diseases were measured by ELISA. The expression of SEMA4D in blood cells and nasal polyp tissues was assessed by flow cytometry and immunohistochemistry, respectively. Generation of soluble SEMA4D was evaluated in matrix metalloproteinase-treated eosinophils. Endothelial cells were stimulated with recombinant SEMA4D, followed by eosinophil transendothelial migration assays. Allergic chronic rhinosinusitis was induced in mice using Aspergillus protease with ovalbumin. The efficacy of treatment with anti-SEMA4D antibody was evaluated histologically and by nasal lavage fluid analysis.

Results: Serum soluble SEMA4D levels were elevated in patients with ECRS and positively correlated with disease severity. Tissue-infiltrated eosinophils in nasal polyps from patients with ECRS stained strongly with anti-SEMA4D antibody. Cell surface expression of SEMA4D on eosinophils from patients with ECRS was reduced, which was due to matrix metalloproteinase-9-mediated cleavage of membrane SEMA4D. Soluble SEMA4D induced eosinophil transendothelial migration. Treatment with anti-SEMA4D antibody ameliorated eosinophilic infiltration in sinus tissues and nasal lavage fluid in the ECRS animal model.

Conclusions: Eosinophil-derived SEMA4D aggravates ECRS. Levels of serum SEMA4D reflect disease severity, and anti-SEMA4D antibody has therapeutic potential as a treatment for ECRS.
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http://dx.doi.org/10.1016/j.jaci.2019.12.893DOI Listing
March 2020

Single-incision laparoscopic colectomy for ascending colon tumor with relapsing polychondritis.

Asian J Endosc Surg 2020 Oct 3;13(4):569-573. Epub 2020 Feb 3.

Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.

A 69-year-old man underwent single-incision laparoscopic colectomy for a colon tumor. He had comorbid relapsing polychondritis, an uncommon and intractable chronic inflammatory disease that shows various symptoms and systemically invades the cartilaginous tissue throughout the body. In this case, the bronchial wall was edematous and the glottis was incompetent. Steroids were also administered. Although the patient had high-risk factors for surgical complications, none occurred during the perioperative period. Once the C-reactive protein value returned to within the normal range after surgery, we reduced the steroid dose. This is the first report of single-incision laparoscopic colectomy for a patient with relapsing polychondritis.
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http://dx.doi.org/10.1111/ases.12788DOI Listing
October 2020

Single Cell Analysis of Neutrophils NETs by Microscopic LSPR Imaging System.

Micromachines (Basel) 2019 Dec 31;11(1). Epub 2019 Dec 31.

Department of Applied Physics, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita 565-0871, Japan.

A simple microengraving cell monitoring method for neutrophil extracellular traps (NETs) released from single neutrophils has been realized using a polydimethylsiloxane (PDMS) microwell array (MWA) sheet on a plasmon chip platform. An imbalance between NETs formation and the succeeding degradation (NETosis) are considered associated with autoimmune disease and its pathogenesis. Thus, an alternative platform that can conduct monitoring of this activity on single cell level at minimum cost but with great sensitivity is greatly desired. The developed MWA plasmon chips allow single cell isolation of neutrophils from 150 µL suspension (6.0 × 10 cells/mL) with an efficiency of 36.3%; 105 microwells with single cell condition. To demonstrate the utility of the chip, trapped cells were incubated between 2 to 4 h after introducing with 100 nM phorbol 12-myristate 13-acetate (PMA) before measurement. Under observation using a hyperspectral imaging system that allows high-throughput screening, the neutrophils stimulated by PMA solution show a significant release of fibrils and NETs after 4 h, with observed maximum areas between 314-758 µm. An average absorption peak wavelength shows a redshift of Δλ = 1.5 nm as neutrophils release NETs.
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http://dx.doi.org/10.3390/mi11010052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019790PMC
December 2019

Development and validation of a deep-learning model for scoring of radiographic finger joint destruction in rheumatoid arthritis.

Rheumatol Adv Pract 2019 22;3(2):rkz047. Epub 2019 Nov 22.

Department of Respiratory Medicine and Clinical Immunology, Internal Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka.

Objective: The purpose of this research was to develop a deep-learning model to assess radiographic finger joint destruction in RA.

Methods: The model comprises two steps: a joint-detection step and a joint-evaluation step. Among 216 radiographs of 108 patients with RA, 186 radiographs were assigned to the training/validation dataset and 30 to the test dataset. In the training/validation dataset, images of PIP joints, the IP joint of the thumb or MCP joints were manually clipped and scored for joint space narrowing (JSN) and bone erosion by clinicians, and then these images were augmented. As a result, 11 160 images were used to train and validate a deep convolutional neural network for joint evaluation. Three thousand seven hundred and twenty selected images were used to train machine learning for joint detection. These steps were combined as the assessment model for radiographic finger joint destruction. Performance of the model was examined using the test dataset, which was not included in the training/validation process, by comparing the scores assigned by the model and clinicians.

Results: The model detected PIP joints, the IP joint of the thumb and MCP joints with a sensitivity of 95.3% and assigned scores for JSN and erosion. Accuracy (percentage of exact agreement) reached 49.3-65.4% for JSN and 70.6-74.1% for erosion. The correlation coefficient between scores by the model and clinicians per image was 0.72-0.88 for JSN and 0.54-0.75 for erosion.

Conclusion: Image processing with the trained convolutional neural network model is promising to assess radiographs in RA.
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http://dx.doi.org/10.1093/rap/rkz047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921374PMC
November 2019

Semaphorin 7A promotes EGFR-TKI resistance in EGFR mutant lung adenocarcinoma cells.

JCI Insight 2018 12 20;3(24). Epub 2018 Dec 20.

Department of Thoracic Oncology and.

Although responses to EGFR tyrosine kinase inhibitors (EGFR-TKIs) are initially positive, 30%-40% of patients with EGFR-mutant tumors do not respond well to EGFR-TKIs, and most lung cancer patients harboring EGFR mutations experience relapse with resistance. Therefore, it is necessary to identify not only the mechanisms underlying EGFR-TKI resistance, but also potentially novel therapeutic targets and/or predictive biomarkers for EGFR-mutant lung adenocarcinoma. We found that the GPI-anchored protein semaphorin 7A (SEMA7A) is highly induced by the EGFR pathway, via mTOR signaling, and that expression levels of SEMA7A in human lung adenocarcinoma specimens were correlated with mTOR activation. Investigations using cell culture and animal models demonstrated that loss or overexpression of SEMA7A made cells less or more resistant to EGFR-TKIs, respectively. The resistance was due to the inhibition of apoptosis by aberrant activation of ERK. The ERK signal was suppressed by knockdown of integrin β1 (ITGB1). Furthermore, in patients with EGFR mutant tumors, higher SEMA7A expression in clinical samples predicted poorer response to EGFR-TKI treatment. Collectively, these data show that the SEMA7A-ITGB1 axis plays pivotal roles in EGFR-TKI resistance mediated by ERK activation and apoptosis inhibition. Moreover, our results reveal the potential utility of SEMA7A not only as a predictive biomarker, but also as a potentially novel therapeutic target in EGFR-mutant lung adenocarcinoma.
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http://dx.doi.org/10.1172/jci.insight.123093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338389PMC
December 2018

OCTA, a sensitive screening for asymptomatic retinopathy, raises alarm over systemic involvements in patients with SLE.

Ann Rheum Dis 2020 02 28;79(2):e17. Epub 2018 Nov 28.

Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Japan.

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http://dx.doi.org/10.1136/annrheumdis-2018-214751DOI Listing
February 2020

SEMA4A promotes eosinophil survival and contributes to eosinophil-mediated allergic diseases.

Allergol Int 2019 Apr 19;68(2):274-276. Epub 2018 Oct 19.

Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka, Japan; Laboratory of Immunopathology, World Premier International Immunology Frontier Research Center, Osaka, Japan; Integrated Frontier Research for Medical Science Division, The Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka, Japan.

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http://dx.doi.org/10.1016/j.alit.2018.10.001DOI Listing
April 2019

Eosinophil-derived neurotoxin enhances airway remodeling in eosinophilic chronic rhinosinusitis and correlates with disease severity.

Int Immunol 2019 02;31(1):33-40

Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka, Japan.

Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis (CRS) that is characterized by intractable nasal polyp formation. Eosinophil-derived neurotoxin (EDN) is an eosinophil granule protein that is closely related to allergic inflammation, but the pathological implications of EDN in ECRS remain unknown. In this study, we evaluated the function of EDN in ECRS pathogenesis and assessed its potential as a disease activity marker. Serum EDN levels were significantly higher in patients with ECRS than in those with other nasal and paranasal diseases, and were positively correlated with clinical disease activity. Production of EDN from isolated human eosinophils was induced by stimulation with IL-5 in vitro. Human nasal epithelial cells were stimulated with EDN, and the resultant changes in gene expression were detected by RNA sequencing. Pathway analysis revealed that the major canonical pathway affected by EDN stimulation was 'regulation of the epithelial-mesenchymal transition pathway'; the only gene in this pathway to be up-regulated was matrix metalloproteinase 9 (MMP-9). Consistent with this, immunostaining analysis revealed intense staining of both EDN and MMP-9 in nasal polyps from patients with ECRS. In conclusion, our data demonstrate that serum EDN level is a useful marker for the evaluation of ECRS severity. Furthermore, EDN induces production of MMP-9 from the nasal epithelium, which may be involved in the pathogenesis of ECRS.
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http://dx.doi.org/10.1093/intimm/dxy061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6364622PMC
February 2019

Apoptosis-derived membrane vesicles drive the cGAS-STING pathway and enhance type I IFN production in systemic lupus erythematosus.

Ann Rheum Dis 2018 10 26;77(10):1507-1515. Epub 2018 Jun 26.

Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.

Objective: Despite the importance of type I interferon (IFN-I) in systemic lupus erythematosus (SLE) pathogenesis, the mechanisms of IFN-I production have not been fully elucidated. Recognition of nucleic acids by DNA sensors induces IFN-I and interferon-stimulated genes (ISGs), but the involvement of cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) and stimulator of interferon genes (STING) in SLE remains unclear. We studied the role of the cGAS-STING pathway in the IFN-I-producing cascade driven by SLE serum.

Methods: We collected sera from patients with SLE (n=64), patients with other autoimmune diseases (n=31) and healthy controls (n=35), and assayed them using a cell-based reporter system that enables highly sensitive detection of IFN-I and ISG-inducing activity. We used Toll-like receptor-specific reporter cells and reporter cells harbouring knockouts of cGAS, STING and IFNAR2 to evaluate signalling pathway-dependent ISG induction.

Results: IFN-I bioactivity and ISG-inducing activities of serum were higher in patients with SLE than in patients with other autoimmune diseases or healthy controls. ISG-inducing activity of SLE sera was significantly reduced in STING-knockout reporter cells, and STING-dependent ISG-inducing activity correlated with disease activity. Double-stranded DNA levels were elevated in SLE. Apoptosis-derived membrane vesicles (AdMVs) from SLE sera had high ISG-inducing activity, which was diminished in cGAS-knockout or STING-knockout reporter cells.

Conclusions: AdMVs in SLE serum induce IFN-I production through activation of the cGAS-STING pathway. Thus, blockade of the cGAS-STING axis represents a promising therapeutic target for SLE. Moreover, our cell-based reporter system may be useful for stratifying patients with SLE with high ISG-inducing activity.
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http://dx.doi.org/10.1136/annrheumdis-2018-212988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161667PMC
October 2018

Semaphorin 6D reverse signaling controls macrophage lipid metabolism and anti-inflammatory polarization.

Nat Immunol 2018 06 18;19(6):561-570. Epub 2018 May 18.

Department of Immunopathology, Immunology Frontier Research Center, Osaka University, Suita City, Osaka, Japan.

Polarization of macrophages into pro-inflammatory or anti-inflammatory states has distinct metabolic requirements, with mechanistic target of rapamycin (mTOR) kinase signaling playing a critical role. However, it remains unclear how mTOR regulates metabolic status to promote polarization of these cells. Here we show that an mTOR-Semaphorin 6D (Sema6D)-Peroxisome proliferator receptor γ (PPARγ) axis plays critical roles in macrophage polarization. Inhibition of mTOR or loss of Sema6D blocked anti-inflammatory macrophage polarization, concomitant with severe impairments in PPARγ expression, uptake of fatty acids, and lipid metabolic reprogramming. Macrophage expression of the receptor Plexin-A4 is responsible for Sema6D-mediated anti-inflammatory polarization. We found that a tyrosine kinase, c-Abl, which associates with the cytoplasmic region of Sema6D, is required for PPARγ expression. Furthermore, Sema6D is important for generation of intestinal resident CX3CR1 macrophages and prevents development of colitis. Collectively, these findings highlight crucial roles for Sema6D reverse signaling in macrophage polarization, coupling immunity, and metabolism via PPARγ.
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http://dx.doi.org/10.1038/s41590-018-0108-0DOI Listing
June 2018

Lysosomal Protein Lamtor1 Controls Innate Immune Responses via Nuclear Translocation of Transcription Factor EB.

J Immunol 2018 06 23;200(11):3790-3800. Epub 2018 Apr 23.

Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan;

Amino acid metabolism plays important roles in innate immune cells, including macrophages. Recently, we reported that a lysosomal adaptor protein, Lamtor1, which serves as the scaffold for amino acid-activated mechanistic target of rapamycin complex 1 (mTORC1), is critical for the polarization of M2 macrophages. However, little is known about how Lamtor1 affects the inflammatory responses that are triggered by the stimuli for TLRs. In this article, we show that Lamtor1 controls innate immune responses by regulating the phosphorylation and nuclear translocation of transcription factor EB (TFEB), which has been known as the master regulator for lysosome and autophagosome biogenesis. Furthermore, we show that nuclear translocation of TFEB occurs in alveolar macrophages of myeloid-specific Lamtor1 conditional knockout mice and that these mice are hypersensitive to intratracheal administration of LPS and bleomycin. Our observation clarified that the amino acid-sensing pathway consisting of Lamtor1, mTORC1, and TFEB is involved in the regulation of innate immune responses.
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http://dx.doi.org/10.4049/jimmunol.1701283DOI Listing
June 2018

The role of semaphorins in immune responses and autoimmune rheumatic diseases.

Nat Rev Rheumatol 2018 Jan 7;14(1):19-31. Epub 2017 Dec 7.

Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.

Semaphorins have a well-characterized role in guiding axon repulsion during development; however, the important contribution of these proteins in immunity is becoming increasingly clear. Immunoregulatory semaphorins, termed 'immune semaphorins', have roles in regulating immune cell activation, differentiation, mobility and migration. These proteins are also intimately associated with the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This Review discusses the pathogenic functions of immune semaphorins, as well as the potential use of these molecules as diagnostic markers and therapeutic targets for the treatment of autoimmune diseases.
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http://dx.doi.org/10.1038/nrrheum.2017.201DOI Listing
January 2018

Lamtor1 Is Critically Required for CD4 T Cell Proliferation and Regulatory T Cell Suppressive Function.

J Immunol 2017 09 2;199(6):2008-2019. Epub 2017 Aug 2.

Department of Immunopathology, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan;

Mechanistic target of rapamycin complex (mTORC)1 integrates intracellular sufficiency of nutrients and regulates various cellular functions. Previous studies using mice with conditional knockout of mTORC1 component proteins (i.e., mTOR, Raptor, and Rheb) gave conflicting results on the roles of mTORC1 in CD4 T cells. Lamtor1 is the protein that is required for amino acid sensing and activation of mTORC1; however, the roles of Lamtor1 in T cells have not been investigated. In this article, we show that Lamtor1-deficient CD4 T cells exhibited marked reductions in proliferation, IL-2 production, mTORC1 activity, and expression of purine- and lipid-synthesis genes. Polarization of Th17 cells, but not Th1 and Th2 cells, diminished following the loss of Lamtor1. Accordingly, -driven Lamtor1-knockout mice exhibited reduced numbers of CD4 and CD8 T cells at rest, and they were completely resistant to experimental autoimmune encephalomyelitis. In contrast, genetic ablation of Lamtor1 in Foxp3 T cells resulted in severe autoimmunity and premature death. Lamtor1-deficient regulatory T cells survived ex vivo as long as wild-type regulatory T cells; however, they exhibited a marked loss of suppressive function and expression of signature molecules, such as CTLA-4. These results indicate that Lamtor1 plays essential roles in CD4 T cells. Our data suggest that Lamtor1 should be considered a novel therapeutic target in immune systems.
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http://dx.doi.org/10.4049/jimmunol.1700157DOI Listing
September 2017

Semaphorin 4D inhibits neutrophil activation and is involved in the pathogenesis of neutrophil-mediated autoimmune vasculitis.

Ann Rheum Dis 2017 Aug 17;76(8):1440-1448. Epub 2017 Apr 17.

Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan.

Objectives: Inappropriate activation of neutrophils plays a pathological role in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The aim of this study was to investigate the functions of semaphorin 4D (SEMA4D) in regulation of neutrophil activation, and its involvement in AAV pathogenesis.

Methods: Serum levels of soluble SEMA4D were evaluated by ELISA. Blood cell-surface expression of membrane SEMA4D was evaluated by flow cytometry. To determine the functional interactions between neutrophil membrane SEMA4D and endothelial plexin B2, wild-type and mice neutrophils were cultured with an endothelial cell line (MS1) stained with SYTOX green, and subjected to neutrophil extracellular trap (NET) formation assays. The efficacy of treating human neutrophils with recombinant plexin B2 was assessed by measuring the kinetic oxidative burst and NET formation assays.

Results: Serum levels of soluble SEMA4D were elevated in patients with AAV and correlated with disease activity scores. Cell-surface expression of SEMA4D was downregulated in neutrophils from patients with AAV, a consequence of proteolytic cleavage of membrane SEMA4D. Soluble SEMA4D exerted pro-inflammatory effects on endothelial cells. Membranous SEMA4D on neutrophils bound to plexin B2 on endothelial cells, and this interaction decreased NET formation. Recombinant plexin B2 suppressed neutrophil Rac1 activation through SEMA4D's intracellular domain, and inhibited pathogen-induced or ANCA-induced oxidative burst and NET formation.

Conclusions: Neutrophil surface SEMA4D functions as a negative regulator of neutrophil activation. Proteolytic cleavage of SEMA4D as observed in patients with AAV may amplify neutrophil-mediated inflammatory responses. SEMA4D is a promising biomarker and potential therapeutic target for AAV.
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http://dx.doi.org/10.1136/annrheumdis-2016-210706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738596PMC
August 2017

Polarization of M2 macrophages requires Lamtor1 that integrates cytokine and amino-acid signals.

Nat Commun 2016 10 12;7:13130. Epub 2016 Oct 12.

Department of Immunopathology, World Premier International Immunology Frontier Research Center, Osaka University, Yamadaoka 2-2, Osaka 565-0871 Japan.

Macrophages play crucial roles in host defence and tissue homoeostasis, processes in which both environmental stimuli and intracellularly generated metabolites influence activation of macrophages. Activated macrophages are classified into M1 and M2 macrophages. It remains unclear how intracellular nutrition sufficiency, especially for amino acid, influences on macrophage activation. Here we show that a lysosomal adaptor protein Lamtor1, which forms an amino-acid sensing complex with lysosomal vacuolar-type H-ATPase (v-ATPase), and is the scaffold for amino acid-activated mTORC1 (mechanistic target of rapamycin complex 1), is critically required for M2 polarization. Lamtor1 deficiency, amino-acid starvation, or inhibition of v-ATPase and mTOR result in defective M2 polarization and enhanced M1 polarization. Furthermore, we identified liver X receptor (LXR) as the downstream target of Lamtor1 and mTORC1. Production of 25-hydroxycholesterol is dependent on Lamtor1 and mTORC1. Our findings demonstrate that Lamtor1 plays an essential role in M2 polarization, coupling immunity and metabolism.
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http://dx.doi.org/10.1038/ncomms13130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5064021PMC
October 2016

LRRK1 is critical in the regulation of B-cell responses and CARMA1-dependent NF-κB activation.

Sci Rep 2016 05 11;6:25738. Epub 2016 May 11.

Department of Immunopathology, World Premier International (WPI) Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.

B-cell receptor (BCR) signaling plays a critical role in B-cell activation and humoral immunity. In this study, we discovered a critical function of leucine-rich repeat kinase 1 (LRRK1) in BCR-mediated immune responses. Lrrk1(-/-) mice exhibited altered B1a-cell development and basal immunoglobulin production. In addition, these mice failed to produce IgG3 antibody in response to T cell-independent type 2 antigen due to defects in IgG3 class-switch recombination. Concomitantly, B cells lacking LRRK1 exhibited a profound defect in proliferation and survival upon BCR stimulation, which correlated with impaired BCR-mediated NF-κB activation and reduced expression of NF-κB target genes including Bcl-xL, cyclin D2, and NFATc1/αA. Furthermore, LRRK1 physically interacted and potently synergized with CARMA1 to enhance NF-κB activation. Our results reveal a critical role of LRRK1 in NF-κB signaling in B cells and the humoral immune response.
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http://dx.doi.org/10.1038/srep25738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863158PMC
May 2016

Oral tacrolimus for the treatment of generalized morphea.

Eur J Dermatol 2016 Jan-Feb;26(1):112-3

Department of Dermatology, Japan Community Healthcare Organization Osaka Hospital.

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http://dx.doi.org/10.1684/ejd.2015.2689DOI Listing
December 2016

mTOR Complex Signaling through the SEMA4A-Plexin B2 Axis Is Required for Optimal Activation and Differentiation of CD8+ T Cells.

J Immunol 2015 Aug 26;195(3):934-43. Epub 2015 Jun 26.

Department of Immunopathology, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Suita City, Osaka 565-0871, Japan; Department of Respiratory Medicine, Allergy, and Rheumatic Disease, Osaka University Graduate School of Medicine, Suita City, Osaka 565-0871, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Suita City, Osaka 565-0871, Japan;

Mammalian target of rapamycin (mTOR) plays crucial roles in activation and differentiation of diverse types of immune cells. Although several lines of evidence have demonstrated the importance of mTOR-mediated signals in CD4(+) T cell responses, the involvement of mTOR in CD8(+) T cell responses is not fully understood. In this study, we show that a class IV semaphorin, SEMA4A, regulates CD8(+) T cell activation and differentiation through activation of mTOR complex (mTORC) 1. SEMA4A(-/-) CD8(+) T cells exhibited impairments in production of IFN-γ and TNF-α and induction of the effector molecules granzyme B, perforin, and FAS-L. Upon infection with OVA-expressing Listeria monocytogenes, pathogen-specific effector CD8(+) T cell responses were significantly impaired in SEMA4A(-/-) mice. Furthermore, SEMA4A(-/-) CD8(+) T cells exhibited reduced mTORC1 activity and elevated mTORC2 activity, suggesting that SEMA4A is required for optimal activation of mTORC1 in CD8(+) T cells. IFN-γ production and mTORC1 activity in SEMA4A(-/-) CD8(+) T cells were restored by administration of recombinant Sema4A protein. In addition, we show that plexin B2 is a functional receptor of SEMA4A in CD8(+) T cells. Collectively, these results not only demonstrate the role of SEMA4A in CD8(+) T cells, but also reveal a novel link between a semaphorin and mTOR signaling.
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http://dx.doi.org/10.4049/jimmunol.1403038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505953PMC
August 2015

Semaphorin 4D Contributes to Rheumatoid Arthritis by Inducing Inflammatory Cytokine Production: Pathogenic and Therapeutic Implications.

Arthritis Rheumatol 2015 Jun;67(6):1481-90

Osaka University Graduate School of Medicine, Osaka, Japan.

Objective: Semaphorin 4D (Sema4D)/CD100 has pleiotropic roles in immune activation, angiogenesis, bone metabolism, and neural development. We undertook this study to investigate the role of Sema4D in rheumatoid arthritis (RA).

Methods: Soluble Sema4D (sSema4D) levels in serum and synovial fluid were analyzed by enzyme-linked immunosorbent assay. Cell surface expression and transcripts of Sema4D were analyzed in peripheral blood cells from RA patients, and immunohistochemical staining of Sema4D was performed in RA synovium. Generation of sSema4D was evaluated in an ADAMTS-4-treated monocytic cell line (THP-1 cells). The efficacy of anti-Sema4D antibody was evaluated in mice with collagen-induced arthritis (CIA).

Results: Levels of sSema4D were elevated in both serum and synovial fluid from RA patients, and disease activity markers were correlated with serum sSema4D levels. Sema4D-expressing cells also accumulated in RA synovium. Cell surface levels of Sema4D on CD3+ and CD14+ cells from RA patients were reduced, although levels of Sema4D transcripts were unchanged. In addition, ADAMTS-4 cleaved cell surface Sema4D to generate sSema4D in THP-1 cells. Soluble Sema4D induced tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) production from CD14+ monocytes. IL-6 and TNFα induced ADAMTS-4 expression in synovial cells. Treatment with an anti-Sema4D antibody suppressed arthritis and reduced proinflammatory cytokine production in CIA.

Conclusion: A positive feedback loop involving sSema4D/IL-6 and TNFα/ADAMTS-4 may contribute to the pathogenesis of RA. The inhibition of arthritis by anti-Sema4D antibody suggests that Sema4D represents a potential therapeutic target for RA.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5032998PMC
http://dx.doi.org/10.1002/art.39086DOI Listing
June 2015

Improvement of health status evaluated by Arthritis Impact Measurement Scale 2 (AIMS-2) and Short Form-36 (SF-36) in patients with rheumatoid arthritis treated with tocilizumab.

Mod Rheumatol 2013 Mar 6;23(2):276-83. Epub 2012 Jun 6.

Division of Nursing, NTT West Osaka Hospital, Osaka, Japan.

Objective: To evaluate the improvement of health status in patients with rheumatoid arthritis (RA) treated with tocilizumab.

Methods: Thirty-nine patients were treated with 8 mg/kg tocilizumab every 4 weeks for 24 weeks. Disease activity was assessed by Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI). Improvement of health status was assessed by Arthritis Impact Measurement Scale 2 (AIMS-2) and Short Form-36 (SF-36).

Results: Tocilizumab improved CDAI and SDAI significantly at week 4 compared with at baseline. In the components of AIMS-2, "physical score", "symptom" and "affect" improved significantly at week 4 compared with at baseline, while "social interaction" did not improve significantly during 24 weeks of tocilizumab therapy. Similarly in SF-36, "bodily pain", "general health", "vitality" and "mental health" improved significantly at week 4. The most correlative component of AIMS-2 with CDAI was "symptom", while "social interaction" did not correlate with CDAI during tocilizumab treatment.

Conclusion: The time-course diversity in improvement of health status should be considered to provide proper healthcare when treated with tocilizumab.
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http://dx.doi.org/10.1007/s10165-012-0674-1DOI Listing
March 2013

A case report of a patient with rheumatoid arthritis complicated with Mycobacterium avium during tocilizumab treatment.

Mod Rheumatol 2011 Dec 12;21(6):655-9. Epub 2011 Apr 12.

Division of Allergy, Rheumatology and Connective Tissue Diseases, Department of Internal Medicine, NTT West Osaka Hospital, 2-6-40 Karasugatsuji, Tennoji-ku, Osaka 543-8922, Japan.

A female patient with rheumatoid arthritis (RA) suffered from Mycobacterium avium (M. avium) infection during tocilizumab treatment. Tocilizumab was discontinued and she was treated with a recommended chemotherapy, resulting in improvement of M. avium. Tocilizumab retreatment did not aggravate M. avium infection, and radiographic abnormalities improved over 1 year after cessation of the recommended therapy. Tocilizumab may be one candidate for intractable RA patients with M. avium if any biologic is required.
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http://dx.doi.org/10.1007/s10165-011-0448-1DOI Listing
December 2011
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