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Targeting Multiple End Organs in Lupus and Other Systemic Rheumatic Diseases by Inhibiting Bruton’s Tyrosine Kinase

Bruton tyrosine kinase (Btk) plays a vital role in activating and differentiating B-cells and regulating signaling in myeloid cells. Indeed, the potential use of Btk inhibitors in preventing lupus has been reported. Here, we extend these observations to 4 additional models of end-organ inflammation:...

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Autores principales: Du, Yong, Lei, Ling, Ding, Huihua, Chen, Yanping, Pathak, Simanta, Hicks, John, Tran, Phuongthy T., Wu, Minghua, Chang, Betty, Wirtz, Uwe, Mohan, Chandra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9304663/
https://www.ncbi.nlm.nih.gov/pubmed/35874767
http://dx.doi.org/10.3389/fimmu.2022.893899
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author Du, Yong
Lei, Ling
Ding, Huihua
Chen, Yanping
Pathak, Simanta
Hicks, John
Tran, Phuongthy T.
Wu, Minghua
Chang, Betty
Wirtz, Uwe
Mohan, Chandra
author_facet Du, Yong
Lei, Ling
Ding, Huihua
Chen, Yanping
Pathak, Simanta
Hicks, John
Tran, Phuongthy T.
Wu, Minghua
Chang, Betty
Wirtz, Uwe
Mohan, Chandra
author_sort Du, Yong
collection PubMed
description Bruton tyrosine kinase (Btk) plays a vital role in activating and differentiating B-cells and regulating signaling in myeloid cells. Indeed, the potential use of Btk inhibitors in preventing lupus has been reported. Here, we extend these observations to 4 additional models of end-organ inflammation: (a) BWF1 lupus nephritis mice, (b) anti-GBM nephritis, (c) bleomycin-induced systemic sclerosis like skin disease, and (d) bleomycin-induced lung disease. In agreement with the previous studies, BTK inhibitor (BTKB66) treatment was effective in treating lupus nephritis in terms of reducing renal damage both functionally and histologically, accompanied by significant decrease in proteinuria. Both low-dose and high-dose BTKB66 profoundly blocked renal disease in the anti-GBM nephritis model, with efficacy that was comparable to that seen with dexamethasone. This study provides the first evidence that BTK inhibition has both therapeutic and preventative effects in bleomycin-induced SSc-like disease, in terms of reducing skin thickness, fibrosis, collagen deposition, and inflammation. Likewise, significantly lower lung inflammatory cell infiltration was observed after treatment with BTKB66. Therapeutic benefit was associated with lower numbers of macrophages, proliferating macrophages and activated T-cells in the respective injured organs. The observation that these immune cells play key roles in driving end organ inflammation in multiple systemic rheumatic diseases have broad implications for the use of BTKB66 in managing patients with systemic rheumatic diseases where multiple end organs are afflicted, including lupus and systemic sclerosis.
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spelling pubmed-93046632022-07-23 Targeting Multiple End Organs in Lupus and Other Systemic Rheumatic Diseases by Inhibiting Bruton’s Tyrosine Kinase Du, Yong Lei, Ling Ding, Huihua Chen, Yanping Pathak, Simanta Hicks, John Tran, Phuongthy T. Wu, Minghua Chang, Betty Wirtz, Uwe Mohan, Chandra Front Immunol Immunology Bruton tyrosine kinase (Btk) plays a vital role in activating and differentiating B-cells and regulating signaling in myeloid cells. Indeed, the potential use of Btk inhibitors in preventing lupus has been reported. Here, we extend these observations to 4 additional models of end-organ inflammation: (a) BWF1 lupus nephritis mice, (b) anti-GBM nephritis, (c) bleomycin-induced systemic sclerosis like skin disease, and (d) bleomycin-induced lung disease. In agreement with the previous studies, BTK inhibitor (BTKB66) treatment was effective in treating lupus nephritis in terms of reducing renal damage both functionally and histologically, accompanied by significant decrease in proteinuria. Both low-dose and high-dose BTKB66 profoundly blocked renal disease in the anti-GBM nephritis model, with efficacy that was comparable to that seen with dexamethasone. This study provides the first evidence that BTK inhibition has both therapeutic and preventative effects in bleomycin-induced SSc-like disease, in terms of reducing skin thickness, fibrosis, collagen deposition, and inflammation. Likewise, significantly lower lung inflammatory cell infiltration was observed after treatment with BTKB66. Therapeutic benefit was associated with lower numbers of macrophages, proliferating macrophages and activated T-cells in the respective injured organs. The observation that these immune cells play key roles in driving end organ inflammation in multiple systemic rheumatic diseases have broad implications for the use of BTKB66 in managing patients with systemic rheumatic diseases where multiple end organs are afflicted, including lupus and systemic sclerosis. Frontiers Media S.A. 2022-07-08 /pmc/articles/PMC9304663/ /pubmed/35874767 http://dx.doi.org/10.3389/fimmu.2022.893899 Text en Copyright © 2022 Du, Lei, Ding, Chen, Pathak, Hicks, Tran, Wu, Chang, Wirtz and Mohan https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Du, Yong
Lei, Ling
Ding, Huihua
Chen, Yanping
Pathak, Simanta
Hicks, John
Tran, Phuongthy T.
Wu, Minghua
Chang, Betty
Wirtz, Uwe
Mohan, Chandra
Targeting Multiple End Organs in Lupus and Other Systemic Rheumatic Diseases by Inhibiting Bruton’s Tyrosine Kinase
title Targeting Multiple End Organs in Lupus and Other Systemic Rheumatic Diseases by Inhibiting Bruton’s Tyrosine Kinase
title_full Targeting Multiple End Organs in Lupus and Other Systemic Rheumatic Diseases by Inhibiting Bruton’s Tyrosine Kinase
title_fullStr Targeting Multiple End Organs in Lupus and Other Systemic Rheumatic Diseases by Inhibiting Bruton’s Tyrosine Kinase
title_full_unstemmed Targeting Multiple End Organs in Lupus and Other Systemic Rheumatic Diseases by Inhibiting Bruton’s Tyrosine Kinase
title_short Targeting Multiple End Organs in Lupus and Other Systemic Rheumatic Diseases by Inhibiting Bruton’s Tyrosine Kinase
title_sort targeting multiple end organs in lupus and other systemic rheumatic diseases by inhibiting bruton’s tyrosine kinase
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9304663/
https://www.ncbi.nlm.nih.gov/pubmed/35874767
http://dx.doi.org/10.3389/fimmu.2022.893899
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