TY - JOUR AU - Futosi, Krisztina AU - Mócsai, Attila TI - Neutrophil IL-26 fuels autoinflammation JF - JOURNAL OF EXPERIMENTAL MEDICINE J2 - J EXP MED VL - 221 PY - 2024 IS - 5 PG - 3 SN - 0022-1007 DO - 10.1084/jem.20240229 UR - https://m2.mtmt.hu/api/publication/34786398 ID - 34786398 AB - Pustular psoriasis is an inflammatory skin disease with features of neutrophil-mediated sterile autoinflammation. In this issue of JEM, Baldo et al. show that this autoinflammation is driven by a vicious cycle through neutrophil-derived IL-26. Pustular psoriasis is an inflammatory skin disease with features of neutrophil-mediated sterile autoinflammation. In this issue of JEM, Baldo et al. (https://doi.org/10.1084/jem.20231464) show that this autoinflammation is driven by a vicious cycle through neutrophil-derived IL-26. LA - English DB - MTMT ER - TY - JOUR AU - Révész, Csaba AU - Kaucsár, Tamás AU - Godó, Mária AU - Bocskai, Krisztián AU - Krenács, Tibor AU - Mócsai, Attila AU - Szénási, Gábor AU - Hamar, Péter TI - Neutrophils and NADPH Oxidases Are Major Contributors to Mild but Not Severe Ischemic Acute Kidney Injury in Mice JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 25 PY - 2024 IS - 5 PG - 17 SN - 1661-6596 DO - 10.3390/ijms25052948 UR - https://m2.mtmt.hu/api/publication/34728797 ID - 34728797 AB - Upregulation of free radical-generating NADPH oxidases (NOX), xanthine oxidoreductase (XOR), and neutrophil infiltration-induced, NOX2-mediated respiratory burst contribute to renal ischemia–reperfusion injury (IRI), but their roles may depend on the severity of IRI. We investigated the role of NOX, XOR, and neutrophils in developing IRI of various severities. C57BL/6 and Mcl-1ΔMyelo neutrophil-deficient mice were used. Oxidases were silenced by RNA interference (RNAi) or pharmacologically inhibited. Kidney function, morphology, immunohistochemistry and mRNA expression were assessed. After reperfusion, the expression of NOX enzymes and XOR increased until 6 h and from 15 h, respectively, while neutrophil infiltration was prominent from 3 h. NOX4 and XOR silencing or pharmacological XOR inhibition did not protect the kidney from IRI. Attenuation of NOX enzyme-induced oxidative stress by apocynin and neutrophil deficiency improved kidney function and ameliorated morphological damage after mild but not moderate/severe IRI. The IR-induced postischemic renal functional impairment (BUN, Lcn-2), tubular necrosis score, inflammation (TNF-α, F4/80), and decreases in the antioxidant enzyme (GPx3) mRNA expression were attenuated by both apocynin and neutrophil deficiency. Inhibition of NOX enzyme-induced oxidative stress or the lack of infiltration by NOX2-expressing neutrophils can attenuate reperfusion injury after mild but not moderate/severe renal IR. LA - English DB - MTMT ER - TY - JOUR AU - Báskay, János AU - Pénzes, Dorottya AU - Kontsek, Endre AU - Pesti, Adrián István AU - Kiss, András AU - Carvalho, Bruna Katherine Guimarães AU - Szócska, Miklós AU - Szabó, Bence Tamás AU - Dobó-Nagy, Csaba AU - Csete, Dániel AU - Mócsai, Attila AU - Németh, Orsolya AU - Pollner, Péter AU - Mijiritsky, Eitan AU - Kivovics, Márton TI - Are Artificial Intelligence-Assisted Three-Dimensional Histological Reconstructions Reliable for the Assessment of Trabecular Microarchitecture? JF - JOURNAL OF CLINICAL MEDICINE J2 - J CLIN MED VL - 13 PY - 2024 IS - 4 PG - 15 SN - 2077-0383 DO - 10.3390/jcm13041106 UR - https://m2.mtmt.hu/api/publication/34596805 ID - 34596805 N1 - Data-Driven Health Division of National Laboratory for Health Security, Health Services Management Training Centre, Semmelweis University, Kútvölgyi út 2, Budapest, 1125, Hungary Department of Biological Physics, Eötvös Loránd University, Pázmány Péter Sétány 1/a, Budapest, 1117, Hungary Department of Community Dentistry, Semmelweis University, Szentkirályi Utca 40, Budapest, 1088, Hungary Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, Üllői út 93, Budapest, 1091, Hungary Department of Oral Diagnostics, Semmelweis University, Szentkirályi Utca 47, Budapest, 1088, Hungary Department of Physiology, Semmelweis University, Tűzoltó u. 34-37, Budapest, 1094, Hungary Department of Head and Neck Surgery and Maxillofacial Surgery, Tel-Aviv Sourasky Medical Center, School of Medicine, Tel Aviv University, Tel Aviv64239, Israel Goldschleger School of Dental Medicine, Faculty of Medicine, Tel Aviv University, Tel Aviv, 39040, Israel Export Date: 7 April 2024 Correspondence Address: Kivovics, M.; Department of Community Dentistry, Szentkirályi Utca 40, Hungary; email: kivovics.marton@semmelweis.hu AB - This study aimed to create a three-dimensional histological reconstruction through the AI-assisted classification of tissues and the alignment of serial sections. The secondary aim was to evaluate if the novel technique for histological reconstruction accurately replicated the trabecular microarchitecture of bone. This was performed by conducting micromorphometric measurements on the reconstruction and comparing the results obtained with those of microCT reconstructions. A bone biopsy sample was harvested upon re-entry following sinus floor augmentation. Following microCT scanning and histological processing, a modified version of the U-Net architecture was trained to categorize tissues on the sections. Detector-free local feature matching with transformers was used to create the histological reconstruction. The micromorphometric parameters were calculated using Bruker’s CTAn software (version 1.18.8.0, Bruker, Kontich, Belgium) for both histological and microCT datasets. Correlation coefficients calculated between the micromorphometric parameters measured on the microCT and histological reconstruction suggest a strong linear relationship between the two with ⍴-values of 0.777, 0.717, 0.705, 0.666, and 0.687 for BV/TV, BS/TV, Tb.Pf Tb.Th, and Tb.Sp, respectively. Bland–Altman and mountain plots suggest good agreement between BV/TV measurements on the two reconstruction methods. This novel method for three-dimensional histological reconstruction provides researchers with a tool that enables the assessment of accurate trabecular microarchitecture and histological information simultaneously. LA - English DB - MTMT ER - TY - JOUR AU - Vikár, Simon AU - Szilveszter, Kata AU - Koszorú, Kamilla AU - Sárdy, Miklós AU - Mócsai, Attila TI - The Syk inhibitor entospletinib abolishes dermal-epidermal separation in a fully human ex vivo model of bullous pemphigoid JF - JOURNAL OF INVESTIGATIVE DERMATOLOGY J2 - J INVEST DERMATOL PY - 2024 SN - 0022-202X DO - 10.1016/j.jid.2024.01.009 UR - https://m2.mtmt.hu/api/publication/34543426 ID - 34543426 N1 - Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, Budapest, Hungary HUN-REN–SU Inflammation Physiology Research Group, Hungarian Research Network, Semmelweis University, Budapest, Hungary Export Date: 23 April 2024 CODEN: JIDEA Correspondence Address: Mócsai, A.; Department of Physiology, Tűzoltó utca 37-47, Hungary; email: mocsai.attila@semmelweis.hu Funding details: 777357 Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFIH, KKP-129954, TKP2021-EGA-24, TKP2021-EGA-29 Funding text 1: We thank Nikolett Szénási and Dorottya Deli for expert technical assistance, Mátka Nagy and Regina Tóth-Kun for help with granulocyte isolation, Enkhbilguun Sodbuyan for help with some of the ex vivo dermal–epidermal separation experiments, as well as colleagues involved in the diagnostic procedures and collection of patient samples. This work was supported by the Hungarian National Research, Development, and Innovation Office (KKP-129954 and TKP2021-EGA-24 to AM and TKP2021-EGA-29 to MS and AM), the EU H2020 IMI2 program (RTCure project number 777357 to AM), and the HUN-REN Hungarian Research Network (to AM). SV was supported by the Hungarian National Academy of Scientist Education and the Hungarian New National Excellence Program. LA - English DB - MTMT ER - TY - JOUR AU - Major, Martin AU - Kivovics, Márton AU - Szabó, Bence Tamás AU - Déri, Tamás AU - Polyák, Melinda AU - Jákob, Noémi AU - Csete, Dániel AU - Mócsai, Attila AU - Németh, Zsolt AU - Szabó, György TI - Surgical Treatment of Multiple Bone Cysts Using a Platelet-Rich Fibrin and BoneAlbumin Composite Graft: A Case Report JF - REPORTS J2 - REPORTS-BASEL VL - 7 PY - 2024 IS - 1 PG - 12 SN - 2571-841X DO - 10.3390/reports7010007 UR - https://m2.mtmt.hu/api/publication/34524564 ID - 34524564 AB - Promising research results have been obtained on the tissue-regeneration properties of PRF (platelet-rich fibrin) in dentistry and maxillofacial surgery. PRF presumably promotes healing and accelerates ossification. In this case report, the patient had a history of Gorlin–Goltz syndrome, also called nevoid basal cell carcinoma syndrome, an autosomal dominant neurocutaneous disease that was known for many years. As a consequence, cysts were detected in both the mandible and maxilla. We performed decompression on this 37-year-old patient, followed by a cystectomy on an extensive lesion in the right angle of the mandible. One cyst from each side of the body mandible and one from the maxilla were completely enucleated, as determined using an intraoral exploration. The resulting bone defect was filled with a composite graft composed of a mixture of A-PRF and a serum albumin-coated bone allograft (BoneAlbumin). The wound was then covered with a PRF membrane. The surgical sites were closed per primam. The postoperative period was uneventful. Biopsies were performed after three and six months of healing for histological micromorphometry analyses. Dental implants were placed at the sampling site. Three months after the implantation, the ossified implants were fitted with superstructures. To date, no complications have appeared with the bone augmentation. The authors interpret from the findings that the combination of A-PRF and BoneAlbumin can be validated as a prosperous bone substitute. It can be safely implanted after a 3-month ossification period. LA - English DB - MTMT ER - TY - JOUR AU - Káposztás, Eszter Gertrúd AU - Balogh, Lili AU - Mócsai, Attila AU - Kemecsei, Éva AU - Jakus, Zoltán AU - Németh, Tamás TI - The selective inhibition of the Syk tyrosine kinase ameliorates experimental autoimmune arthritis JF - FRONTIERS IN IMMUNOLOGY J2 - FRONT IMMUNOL VL - 14 PY - 2023 PG - 12 SN - 1664-3224 DO - 10.3389/fimmu.2023.1279155 UR - https://m2.mtmt.hu/api/publication/34424360 ID - 34424360 AB - Autoimmune arthritis – such as rheumatoid arthritis – affect a significant proportion of the population, which can cause everyday joint pain, decreased mobility and reduced quality of life. Despite having more and more therapeutic options available, there are still a lot of patients who cannot reach remission or low disease activity by current therapies. This causes an urgent need for the development of new treatment options. The Syk tyrosine kinase plays an essential role in B cell receptor, Fc receptor and integrin signaling. It has been shown that the hematopoietic cell-specific deletion of Syk resulted in a complete protection against autoantibody-induced experimental arthritis. This prompted us to test the effect of entospletinib, a second generation, Syk-selective inhibitor, which has a tolerable safety profile according to hematological clinical trials, in experimental autoimmune arthritis. We found that entospletinib dose-dependently decreased the macroscopic signs of joint inflammation, while it did not affect the health status of the animals. In line with these findings, local neutrophil accumulation and cytokine levels were reduced compared to the vehicle-treated group, while macrophage accumulation and synovial fibroblast numbers were not significantly altered. Meanwhile, entospletinib dose-dependently decreased the cell responses of immune complex- or integrin ligand-activated neutrophils. Overall, we found that selective Syk inhibition by entospletinib reduced the activity of autoantibody-induced experimental arthritis, which seems to be based mainly on the effect of the inhibitor on neutrophil functions. Our data raise the possibility that entospletinib could be a good drug candidate in the treatment of human autoimmune arthritis. LA - English DB - MTMT ER - TY - JOUR AU - Florez-Barros, F. AU - Bearder, S. AU - Kull, B. AU - Freeman, A. AU - Mócsai, Attila AU - Robson, M.G. TI - The authors reply JF - KIDNEY INTERNATIONAL J2 - KIDNEY INT VL - 104 PY - 2023 IS - 4 SP - 856 EP - 857 PG - 2 SN - 0085-2538 DO - 10.1016/j.kint.2023.07.009 UR - https://m2.mtmt.hu/api/publication/34144235 ID - 34144235 LA - English DB - MTMT ER - TY - JOUR AU - Czárán, Domonkos Tamás AU - Sasvári, Péter AU - Horváth, Ádám István AU - Ella, Krisztina AU - Südy, Ágnes AU - Borbély, Éva AU - Rusznák, Kitti AU - Czéh, Boldizsár AU - Mócsai, Attila AU - Helyes, Zsuzsanna AU - Csépányi-Kömi, Roland TI - Lacking ARHGAP25 Mitigates the Symptoms of Autoantibodyinduced Arthritis in Mice JF - FRONTIERS IN IMMUNOLOGY J2 - FRONT IMMUNOL VL - 14 PY - 2023 PG - 13 SN - 1664-3224 DO - 10.3389/fimmu.2023.1182278 UR - https://m2.mtmt.hu/api/publication/33780028 ID - 33780028 N1 - Department of Physiology, Semmelweis University, Budapest, Hungary Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Pécs, Hungary National Laboratory for Drug Research and Development, Budapest, Hungary Histology and Light Microscopy Core Facility, Szentágothai Research Centre, University of Pécs, Pécs, Hungary Department of Laboratory Medicine, Medical School, University of Pécs, Pécs, Hungary Chronic Pain Research Group, Eötvös Loránd Research Network, University of Pécs, Pécs, Hungary PharmInVivo Ltd, Pécs, Hungary Export Date: 21 March 2024 Correspondence Address: Csépányi-Kömi, R.; Department of Physiology, Hungary; email: csepanyi-komi.roland@med.semmelweis-univ.hu AB - Despite intensive research on rheumatoid arthritis, the pathomechanism of the disease is still not fully understood and the treatment has not been completely resolved. Previously we demonstrated that the GTPase-activating protein, ARHGAP25 has a crucial role in the regulation of basic phagocyte functions. Here we investigate the role of ARHGAP25 in the complex inflammatory process of autoantibody-induced arthritis.Wild-type and ARHGAP25 deficient (KO) mice on a C57BL/6 background, as well as bone marrow chimeric mice, were treated i.p. with the K/BxN arthritogenic or control serum, and the severity of inflammation and pain-related behavior was measured. Histology was prepared, leukocyte infiltration, cytokine production, myeloperoxidase activity, and superoxide production were determined, and comprehensive western blot analysis was conducted.In the absence of ARHGAP25, the severity of inflammation, joint destruction, and mechanical hyperalgesia significantly decreased, similarly to phagocyte infiltration, IL-1β, and MIP-2 levels in the tibiotarsal joint, whereas superoxide production or myeloperoxidase activity was unchanged. We observed a significantly mitigated phenotype in KO bone marrow chimeras as well. In addition, fibroblast-like synoviocytes showed comparable expression of ARHGAP25 to neutrophils. Significantly reduced ERK1/2, MAPK, and I-κB protein signals were detected in the arthritic KO mouse ankles.Our findings suggest that ARHGAP25 has a key role in the pathomechanism of autoantibody-induced arthritis in which it regulates inflammation via the I-κB/NF-κB/IL-1β axis with the involvement of both immune cells and fibroblast-like synoviocytes. LA - English DB - MTMT ER - TY - JOUR AU - Futosi, Krisztina AU - Bajza, Boglárka AU - Deli, Dorottya AU - Erdélyi, András AU - Tusnády, Simon AU - Mócsai, Attila TI - Analysis of intracellular tyrosine phosphorylation in circulating neutrophils as a rapid assay for the in vivo effect of oral tyrosine kinase inhibitors JF - FRONTIERS IN PHARMACOLOGY J2 - FRONT PHARMACOL VL - 14 PY - 2023 PG - 14 SN - 1663-9812 DO - 10.3389/fphar.2023.1056154 UR - https://m2.mtmt.hu/api/publication/33777508 ID - 33777508 AB - Tyrosine kinases are crucial signaling components of diverse biological processes and are major therapeutic targets in various malignancies and immune-mediated disorders. A critical step of development of novel tyrosine kinase inhibitors is the transition from the confirmation of the in vitro effects of drug candidates to the analysis of their in vivo efficacy. To facilitate this transition, we have developed a rapid in vivo assay for the analysis of the effect of oral tyrosine kinase inhibitors on basal tyrosine phosphorylation of circulating mouse neutrophils. The assay uses a single drop of peripheral blood without sacrificing the mice. Flow cytometry using intracellular staining by fluorescently labeled anti-phosphotyrosine antibodies revealed robust basal tyrosine phosphorylation in resting circulating neutrophils. This signal was abrogated by the use of isotype control antibodies or by pre-saturation of the anti-phosphotyrosine antibodies with soluble phosphotyrosine amino acids or tyrosine-phosphorylated peptides. Basal tyrosine phosphorylation was dramatically reduced in neutrophils of triple knockout mice lacking the Src-family tyrosine kinases Hck, Fgr, and Lyn. Neutrophil tyrosine phosphorylation was also abrogated by oral administration of the Abl/Src-family inhibitor dasatinib, a clinically used anti-leukemic agent. Detailed dose-response and kinetic studies revealed half-maximal reduction of neutrophil tyrosine phosphorylation by 2.9 mg/kg dasatinib, with maximal reduction observed 2 h after inhibitor administration. Taken together, our assay allows highly efficient analysis of the in vivo effect of orally administered tyrosine kinase inhibitors, and may be used as a suitable alternative to other existing approaches. LA - English DB - MTMT ER - TY - JOUR AU - Futosi, Krisztina AU - Németh, Tamás AU - Horváth, Ádám István AU - Abram, Clare L AU - Tusnády, Simon AU - Lowell, Clifford A AU - Helyes, Zsuzsanna AU - Mócsai, Attila TI - Myeloid Src-family kinases are critical for neutrophil-mediated autoinflammation in gout and motheaten models. JF - JOURNAL OF EXPERIMENTAL MEDICINE J2 - J EXP MED VL - 220 PY - 2023 IS - 7 SN - 0022-1007 DO - 10.1084/jem.20221010 UR - https://m2.mtmt.hu/api/publication/33770181 ID - 33770181 N1 - Funding Agency and Grant Number: Hungarian Ministry of National Economy [VEKOP-2.3.2-16-2016-00002]; Hungarian National Research, Development and Innovation Fund [KKP-129954, TKP2021-EGA-24, FK132251, TKP2021-EGA-29, K-138046, TKP2021-EGA-16]; European Social Fund; European Union H2020 IMI2 program (RTCure project) [UNKP-20-5-SE-4]; Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences; New National Excellence Program of the Ministry for Innovation and Technology [UNKP-21-5-SE-2, 2017-1.2.1-NKP-2017-00002]; National Brain Research Program [EFOP-3.6.1.-16-2016-00004]; Hungarian National Academy of Scientist Education; [777357] Funding text: This work was supported by the Hungarian Ministry of National Economy (VEKOP-2.3.2-16-2016-00002 to A. Mocsai), the Hungarian National Research, Development and Innovation Fund (KKP-129954 and TKP2021-EGA-24 to A. Mocsai, FK132251 and TKP2021-EGA-29 to T. Nemeth, K-138046 and TKP2021-EGA-16 to Z. Helyes), the European Social Fund (EFOP-3.6.1.-16-2016-00004), the European Union H2020 IMI2 program (RTCure project No. 777357), the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences (to K. Futosi and T. Nemeth), the New National Excellence Program of the Ministry for Innovation and Technology (UNKP-20-5-SE-4 and UNKP-21-5-SE-2 to T. Nemeth), and the National Brain Research Program (2017-1.2.1-NKP-2017-00002 to Z. Helyes). S. Tusnady was supported by the Hungarian National Academy of Scientist Education. AB - Autoinflammatory diseases include a number of monogenic systemic inflammatory diseases, as well as acquired autoinflammatory diseases such as gout. Here, we show that the myeloid Src-family kinases Hck, Fgr, and Lyn are critical for experimental models of gout, as well as for genetically determined systemic inflammation in the Ptpn6me-v/me-v (motheaten viable) mouse model. The Hck-/-Fgr-/-Lyn-/- mutation abrogated various monosodium urate (MSU) crystal-induced pro-inflammatory responses of neutrophils, and protected mice from the development of gouty arthritis. The Src-family inhibitor dasatinib abrogated MSU crystal-induced responses of human neutrophils and reduced experimental gouty arthritis in mice. The Hck-/-Fgr-/-Lyn-/- mutation also abrogated spontaneous inflammation and prolonged the survival of the Ptpn6me-v/me-v mice. Spontaneous adhesion and superoxide release of Ptpn6me-v/me-v neutrophils were also abolished by the Hck-/-Fgr-/-Lyn-/- mutation. Excessive activation of tyrosine phosphorylation pathways in myeloid cells may characterize a subset of autoinflammatory diseases. LA - English DB - MTMT ER -