المؤلفون: Eszter Káposztás, Lili Balogh, Attila Mócsai, Éva Kemecsei, Zoltán Jakus, Tamás Németh

المصدر: Frontiers in Immunology, Vol 14 (2023)

مصطلحات موضوعية: rheumatoid arthritis, SYK (spleen tyrosine kinase), inhibitor, treatment, neutrophils, Immunologic diseases. Allergy, RC581-607

الوصف: 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.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fimmu.2023.1279155/fullTest; https://doaj.org/toc/1664-3224Test

الوصول الحر: https://doaj.org/article/c22db53efe16481cb6d60322987e3845Test

المؤلفون: Jing Wang, Bomiao Ju, Li Zhu, Hanchao Li, Jing Luo, Jing Zhang, Nan Hu, Lingfei Mo, Yanhua Wang, Ying Pan, Jing Huang, Xiaohong Lv, Dan Pu, Zhiming Hao, Lan He, Yuanyuan Li

المصدر: Frontiers in Pharmacology, Vol 14 (2023)

مصطلحات موضوعية: B lymphocytes, belimumab, systemic lupus erythematosus, SYK (spleen tyrosine kinase), Akt, Therapeutics. Pharmacology, RM1-950

الوصف: Objective: To examine the kinetics of B cell subsets and activation markers in the early stage of belimumab treatment and their correction with treatment response.Methods: We enrolled 27 systemic lupus erythematosus (SLE) patients receiving 6 months belimumab treatment. Flow cytometry was used to test their B cell subsets and activation markers (including CD40, CD80, CD95, CD21low, CD22, p-SYK and p-AKT).Results: During belimumab treatment, SLEDAI-2K declined, the proportions of CD19+ B cells and naïve B cells decreased, whereas the switched memory B cells and non-switched B cells increased. The larger variations of the B cell subsets and the activation markers were in the first 1 month than the other later time frames. The ratio of p-SYK/p-AKT on non-switched B cell at 1 month was associated with the SLEDAI-2K decline rate in the 6 months of belimumab treatment.Conclusion: B cell hyperactivity was rapidly inhibited in the early stage of belimumab treatment, and the ratio of p-SYK/p-AKT may predict SLEDAI-2K decline.Clinical Trial Registration:https://www.clinicaltrials.gov/ct2/show/NCT04893161?term=NCT04893161&draw=2&rank=1Test; identifier: NCT04893161.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fphar.2023.1080730/fullTest; https://doaj.org/toc/1663-9812Test

الوصول الحر: https://doaj.org/article/1a3bfd50a4a3427ab5c34827844c3e85Test

المؤلفون: Ryunosuke Muro, Tomoya Narita, Takeshi Nitta, Hiroshi Takayanagi

المصدر: Frontiers in Immunology, Vol 13 (2023)

مصطلحات موضوعية: γδT cell, TCR signal, SYK (spleen tyrosine kinase), IL-17, thymus, Immunologic diseases. Allergy, RC581-607

الوصف: The γδT cells that produce IL-17 (γδT17 cells) play a key role in various pathophysiologic processes in host defense and homeostasis. The development of γδT cells in the thymus requires γδT cell receptor (γδTCR) signaling mediated by the spleen tyrosine kinase (Syk) family proteins, Syk and Zap70. Here, we show a critical role of Syk in the early phase of γδT cell development using mice deficient for Syk specifically in lymphoid lineage cells (Syk-conditional knockout (cKO) mice). The development of γδT cells in the Syk-cKO mice was arrested at the precursor stage where the expression of Rag genes and αβT-lineage-associated genes were retained, indicating that Syk is required for γδT-cell lineage commitment. Loss of Syk in γδT cells weakened TCR signal-induced phosphorylation of Erk and Akt, which is mandatory for the thymic development of γδT17 cells. Syk-cKO mice exhibited a loss of γδT17 cells in the thymus as well as throughout the body, and thereby are protected from γδT17-dependent psoriasis-like skin inflammation. Collectively, our results indicate that Syk is a key player in the lineage commitment of γδT cells and the priming of γδT17 cell differentiation.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fimmu.2022.1045881/fullTest; https://doaj.org/toc/1664-3224Test

الوصول الحر: https://doaj.org/article/d71c9318ace64030808788c26cc88a1cTest

المؤلفون: Mariano Prado Acosta, Guillaume Goyette-Desjardins, Jörg Scheffel, Anne Dudeck, Jürgen Ruland, Bernd Lepenies

المصدر: Frontiers in Immunology, Vol 12 (2021)

مصطلحات موضوعية: Lactobacillus brevis, Mincle, Syk (spleen tyrosine kinase), CARD9, S-layer, antigen presenting cell, Immunologic diseases. Allergy, RC581-607

الوصف: C-type lectin receptors (CLRs) are pattern recognition receptors that are crucial in the innate immune response. The gastrointestinal tract contributes significantly to the maintenance of immune homeostasis; it is the shelter for billions of microorganisms including many genera of Lactobacillus sp. Previously, it was shown that host-CLR interactions with gut microbiota play a crucial role in this context. The Macrophage-inducible C-type lectin (Mincle) is a Syk-coupled CLR that contributes to sensing of mucosa-associated commensals. In this study, we identified Mincle as a receptor for the Surface (S)-layer of the probiotic bacteria Lactobacillus brevis modulating GM-CSF bone marrow-derived cells (BMDCs) functions. We found that the S-layer/Mincle interaction led to a balanced cytokine response in BMDCs by triggering the release of both pro- and anti-inflammatory cytokines. In contrast, BMDCs derived from Mincle−/−, CARD9−/− or conditional Syk−/− mice failed to maintain this balance, thus leading to an increased production of the pro-inflammatory cytokines TNF and IL-6, whereas the levels of the anti-inflammatory cytokines IL-10 and TGF-β were markedly decreased. Importantly, this was accompanied by an altered CD4+ T cell priming capacity of Mincle−/− BMDCs resulting in an increased CD4+ T cell IFN-γ production upon stimulation with L. brevis S-layer. Our results contribute to the understanding of how commensal bacteria regulate antigen-presenting cell (APC) functions and highlight the importance of the Mincle/Syk/Card9 axis in APCs as a key factor in host-microbiota interactions.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fimmu.2021.602067/fullTest; https://doaj.org/toc/1664-3224Test

الوصول الحر: https://doaj.org/article/04360362cc8a4195adbd253d9859ddf7Test

المؤلفون: Prado Acosta, Mariano, Goyette-Desjardins, Guillaume, Scheffel, Jörg, Dudeck, Anne, Ruland, Jürgen, Lepenies, Bernd

مصطلحات موضوعية: article, ddc:630, Hochschulbibliographie allgemein, Verzeichnis wissenschaftlicher Veröffentlichungen, Antigen-Presenting Cells, CD4-Positive T-Lymphocytes, Bone Marrow Cells, Animals, Mice, Knockout, Membrane Glycoproteins, Lectins, C-Type, Membrane Proteins, Cytokines, Signal Transduction, Lactobacillus brevis, CARD Signaling Adaptor Proteins, Syk Kinase, s-layer, Antigen presenting cell, Mincle, Card9, Syk (Spleen Tyrosine Kinase)

الوقت: 2021

الوصف: C-type lectin receptors (CLRs) are pattern recognition receptors that are crucial in the innate immune response. The gastrointestinal tract contributes significantly to the maintenance of immune homeostasis; it is the shelter for billions of microorganisms including many genera of Lactobacillus sp. Previously, it was shown that host-CLR interactions with gut microbiota play a crucial role in this context. The Macrophage-inducible C-type lectin (Mincle) is a Syk-coupled CLR that contributes to sensing of mucosa-associated commensals. In this study, we identified Mincle as a receptor for the Surface (S)-layer of the probiotic bacteria Lactobacillus brevis modulating GM-CSF bone marrow-derived cells (BMDCs) functions. We found that the S-layer/Mincle interaction led to a balanced cytokine response in BMDCs by triggering the release of both pro- and anti-inflammatory cytokines. In contrast, BMDCs derived from Mincle-/-, CARD9-/- or conditional Syk-/- mice failed to maintain this balance, thus leading to an increased production of the pro-inflammatory cytokines TNF and IL-6, whereas the levels of the anti-inflammatory cytokines IL-10 and TGF-β were markedly decreased. Importantly, this was accompanied by an altered CD4+ T cell priming capacity of Mincle-/- BMDCs resulting in an increased CD4+ T cell IFN-γ production upon stimulation with L. brevis S-layer. Our results contribute to the understanding of how commensal bacteria regulate antigen-presenting cell (APC) functions and highlight the importance of the Mincle/Syk/Card9 axis in APCs as a key factor in host-microbiota interactions.

العلاقة: Frontiers in immunology -- Front Immunol -- http://www.frontiersin.org/immunologyTest -- https://www.ncbi.nlm.nih.gov/pmc/journals/1754Test/ -- http://www.bibliothek.uni-regensburg.de/ezeit/?2606827Test -- 2606827-8 -- 1664-3224; https://doi.org/10.3389/fimmu.2021.602067Test; https://elib.tiho-hannover.de/receive/tiho_mods_00005083Test; https://elib.tiho-hannover.de/servlets/MCRFileNodeServlet/tiho_derivate_00001167/fimmu-12-602067.pdfTest; https://europepmc.org/articles/PMC7957004Test; https://www.frontiersin.org/articles/10.3389/fimmu.2021.602067/fullTest

الإتاحة: https://doi.org/10.3389/fimmu.2021.602067Test
https://elib.tiho-hannover.de/receive/tiho_mods_00005083Test
https://elib.tiho-hannover.de/servlets/MCRFileNodeServlet/tiho_derivate_00001167/fimmu-12-602067.pdfTest
https://europepmc.org/articles/PMC7957004Test

المؤلفون: Dániel Csete, Edina Simon, Ahmad Alatshan, Petra Aradi, Csaba Dobó-Nagy, Zoltán Jakus, Szilvia Benkő, Dávid S. Győri, Attila Mócsai

المصدر: Frontiers in Immunology, Vol 10 (2019)

مصطلحات موضوعية: SYK (spleen tyrosine kinase), tyrosine kinase, osteoclasts, Cre-Lox, in vivo, mice, Immunologic diseases. Allergy, RC581-607

الوصف: Syk is a non-receptor tyrosine kinase critically involved in signaling by various immunoreceptors including B-cell-receptors and activating Fc-receptors. We have previously shown that Syk also mediates immunoreceptor-like signals required for the in vitro development and function of osteoclasts. However, the perinatal lethality of Syk−/− mice precluded the analysis of the role of Syk in in vivo bone metabolism. To overcome that problem, we generated mice with osteoclast-specific (SykΔOC) or hematopoietic (SykΔHaemo) Syk deficiency by conditional deletion of Syk using Cre recombinase expressed under the control of the Ctsk or Vav1 promoter, respectively. Micro-CT analysis revealed increased bone trabecular density in both SykΔOC and SykΔHaemo mice, although hematopoietic Syk deficiency caused a more severe phenotype than osteoclast-specific Syk deficiency. Osteoclast-specific Syk deficiency reduced, whereas hematopoietic Syk deficiency completely blocked in vitro development of osteoclasts. Both interventions inhibited the resorptive activity of osteoclasts and osteoclast-specific gene expression. Kinetic analysis of Syk protein levels, Cre expression and the genomic deletion of the Sykflox allele revealed complete and early deletion of Syk from SykΔHaemo osteoclasts whereas Syk was incompletely deleted at a later stage of osteoclast development from SykΔOC cultures. Those results provide an explanation for the in vivo and in vitro difference between the SykΔOC and SykΔHaemo mutant strains and suggest late activation of, and incomplete target gene deletion upon, osteoclast-specific Cre expression driven by the Ctsk promoter. Taken together, our results indicate that Syk plays an indispensable role in osteoclast-mediated in vivo bone resorption and suggest that Syk-specific inhibitors may provide therapeutic benefit in inflammatory and other diseases characterized by excessive osteoclast-mediated bone resorption.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/article/10.3389/fimmu.2019.00937/fullTest; https://doaj.org/toc/1664-3224Test

الوصول الحر: https://doaj.org/article/8f75834120254531bf66331caf148172Test

المؤلفون: Eszter Káposztás, Lili Balogh, Attila Mócsai, Éva Kemecsei, Zoltán Jakus, Tamás Németh

مصطلحات موضوعية: Immunology, Applied Immunology (incl. Antibody Engineering, Xenotransplantation and T-cell Therapies), Autoimmunity, Cellular Immunology, Humoural Immunology and Immunochemistry, Immunogenetics (incl. Genetic Immunology), Innate Immunity, Transplantation Immunology, Tumour Immunology, Immunology not elsewhere classified, Genetic Immunology, Animal Immunology, Veterinary Immunology, rheumatoid arthritis, SYK (spleen tyrosine kinase), inhibitor, treatment, neutrophils

الوصف: 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.

العلاقة: https://figshare.com/articles/figure/Image_1_The_selective_inhibition_of_the_Syk_tyrosine_kinase_ameliorates_experimental_autoimmune_arthritis_tif/24719217Test

الإتاحة: https://doi.org/10.3389/fimmu.2023.1279155.s001Test
https://figshare.com/articles/figure/Image_1_The_selective_inhibition_of_the_Syk_tyrosine_kinase_ameliorates_experimental_autoimmune_arthritis_tif/24719217Test

المؤلفون: Ryunosuke Muro (707582), Tomoya Narita (9203819), Takeshi Nitta (55030), Hiroshi Takayanagi (261902)

مصطلحات موضوعية: Immunology, Applied Immunology (incl. Antibody Engineering, Xenotransplantation and T-cell Therapies), Autoimmunity, Cellular Immunology, Humoural Immunology and Immunochemistry, Immunogenetics (incl. Genetic Immunology), Innate Immunity, Transplantation Immunology, Tumour Immunology, Immunology not elsewhere classified, Genetic Immunology, Animal Immunology, Veterinary Immunology, γδT cell, TCR signal, SYK (spleen tyrosine kinase), IL-17, thymus

الوصف: The γδT cells that produce IL-17 (γδT17 cells) play a key role in various pathophysiologic processes in host defense and homeostasis. The development of γδT cells in the thymus requires γδT cell receptor (γδTCR) signaling mediated by the spleen tyrosine kinase (Syk) family proteins, Syk and Zap70. Here, we show a critical role of Syk in the early phase of γδT cell development using mice deficient for Syk specifically in lymphoid lineage cells (Syk-conditional knockout (cKO) mice). The development of γδT cells in the Syk-cKO mice was arrested at the precursor stage where the expression of Rag genes and αβT-lineage-associated genes were retained, indicating that Syk is required for γδT-cell lineage commitment. Loss of Syk in γδT cells weakened TCR signal-induced phosphorylation of Erk and Akt, which is mandatory for the thymic development of γδT17 cells. Syk-cKO mice exhibited a loss of γδT17 cells in the thymus as well as throughout the body, and thereby are protected from γδT17-dependent psoriasis-like skin inflammation. Collectively, our results indicate that Syk is a key player in the lineage commitment of γδT cells and the priming of γδT17 cell differentiation.

العلاقة: https://figshare.com/articles/figure/Image_6_Spleen_tyrosine_kinase_mediates_the_TCR_signaling_required_for_T_cell_commitment_and_T17_differentiation_tif/21876684Test

الإتاحة: https://doi.org/10.3389/fimmu.2022.1045881.s006Test

المؤلفون: Ryunosuke Muro, Tomoya Narita, Takeshi Nitta, Hiroshi Takayanagi

مصطلحات موضوعية: Immunology, Applied Immunology (incl. Antibody Engineering, Xenotransplantation and T-cell Therapies), Autoimmunity, Cellular Immunology, Humoural Immunology and Immunochemistry, Immunogenetics (incl. Genetic Immunology), Innate Immunity, Transplantation Immunology, Tumour Immunology, Immunology not elsewhere classified, Genetic Immunology, Animal Immunology, Veterinary Immunology, γδT cell, TCR signal, SYK (spleen tyrosine kinase), IL-17, thymus

الوصف: The γδT cells that produce IL-17 (γδT17 cells) play a key role in various pathophysiologic processes in host defense and homeostasis. The development of γδT cells in the thymus requires γδT cell receptor (γδTCR) signaling mediated by the spleen tyrosine kinase (Syk) family proteins, Syk and Zap70. Here, we show a critical role of Syk in the early phase of γδT cell development using mice deficient for Syk specifically in lymphoid lineage cells (Syk-conditional knockout (cKO) mice). The development of γδT cells in the Syk-cKO mice was arrested at the precursor stage where the expression of Rag genes and αβT-lineage-associated genes were retained, indicating that Syk is required for γδT-cell lineage commitment. Loss of Syk in γδT cells weakened TCR signal-induced phosphorylation of Erk and Akt, which is mandatory for the thymic development of γδT17 cells. Syk-cKO mice exhibited a loss of γδT17 cells in the thymus as well as throughout the body, and thereby are protected from γδT17-dependent psoriasis-like skin inflammation. Collectively, our results indicate that Syk is a key player in the lineage commitment of γδT cells and the priming of γδT17 cell differentiation.

العلاقة: https://figshare.com/articles/figure/Image_4_Spleen_tyrosine_kinase_mediates_the_TCR_signaling_required_for_T_cell_commitment_and_T17_differentiation_tif/21876678Test

الإتاحة: https://doi.org/10.3389/fimmu.2022.1045881.s004Test
https://figshare.com/articles/figure/Image_4_Spleen_tyrosine_kinase_mediates_the_TCR_signaling_required_for_T_cell_commitment_and_T17_differentiation_tif/21876678Test

المؤلفون: Jing Wang, Bomiao Ju, Li Zhu, Hanchao Li, Jing Luo, Jing Zhang, Nan Hu, Lingfei Mo, Yanhua Wang, Ying Pan, Jing Huang, Xiaohong Lv, Dan Pu, Zhiming Hao, Lan He, Yuanyuan Li

مصطلحات موضوعية: Pharmacology, Basic Pharmacology, Clinical Pharmacology and Therapeutics, Clinical Pharmacy and Pharmacy Practice, Pharmaceutical Sciences, Pharmacogenomics, Toxicology (incl. Clinical Toxicology), Pharmacology and Pharmaceutical Sciences not elsewhere classified, B lymphocytes, belimumab, systemic lupus erythematosus, SYK (spleen tyrosine kinase), Akt

الوصف: Objective: To examine the kinetics of B cell subsets and activation markers in the early stage of belimumab treatment and their correction with treatment response. Methods: We enrolled 27 systemic lupus erythematosus (SLE) patients receiving 6 months belimumab treatment. Flow cytometry was used to test their B cell subsets and activation markers (including CD40, CD80, CD95, CD21 low , CD22, p-SYK and p-AKT). Results: During belimumab treatment, SLEDAI-2K declined, the proportions of CD19 + B cells and naïve B cells decreased, whereas the switched memory B cells and non-switched B cells increased. The larger variations of the B cell subsets and the activation markers were in the first 1 month than the other later time frames. The ratio of p-SYK/p-AKT on non-switched B cell at 1 month was associated with the SLEDAI-2K decline rate in the 6 months of belimumab treatment. Conclusion: B cell hyperactivity was rapidly inhibited in the early stage of belimumab treatment, and the ratio of p-SYK/p-AKT may predict SLEDAI-2K decline. Clinical Trial Registration:https://www.clinicaltrials.gov/ct2/show/NCT04893161?term=NCT04893161&draw=2&rank=1Test; identifier: NCT04893161.

العلاقة: https://figshare.com/articles/figure/Image1_The_rapid_inhibition_of_B-cell_activation_markers_by_belimumab_was_associated_with_disease_control_in_systemic_lupus_erythematosus_patients_JPEG/22108109Test

الإتاحة: https://doi.org/10.3389/fphar.2023.1080730.s001Test
https://figshare.com/articles/figure/Image1_The_rapid_inhibition_of_B-cell_activation_markers_by_belimumab_was_associated_with_disease_control_in_systemic_lupus_erythematosus_patients_JPEG/22108109Test