Bruton’s tyrosine kinase inhibition reduces disease severity in a model of secondary progressive autoimmune demyelination
Abstract Bruton’s tyrosine kinase (BTK) is an emerging target in multiple sclerosis (MS). Alongside its role in B cell receptor signaling and B cell development, BTK regulates myeloid cell activation and inflammatory responses. Here we demonstrate efficacy of BTK inhibition in a model of secondary p...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-07-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-023-01614-w |
| _version_ | 1797778639594455040 |
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| author | Kirsten Scarlett Evonuk Sen Wang Josh Mattie C. J. Cracchiolo Reine Mager Željko Ferenčić Ethan Sprague Brandon Carrier Kai Schofield Evelyn Martinez Zachary Stewart Tara Petrosino Gregory Andrew Johnson Isharat Yusuf Warren Plaisted Zachary Naiman Timothy Delp Laura Carter Suzana Marušić |
| author_facet | Kirsten Scarlett Evonuk Sen Wang Josh Mattie C. J. Cracchiolo Reine Mager Željko Ferenčić Ethan Sprague Brandon Carrier Kai Schofield Evelyn Martinez Zachary Stewart Tara Petrosino Gregory Andrew Johnson Isharat Yusuf Warren Plaisted Zachary Naiman Timothy Delp Laura Carter Suzana Marušić |
| author_sort | Kirsten Scarlett Evonuk |
| collection | DOAJ |
| description | Abstract Bruton’s tyrosine kinase (BTK) is an emerging target in multiple sclerosis (MS). Alongside its role in B cell receptor signaling and B cell development, BTK regulates myeloid cell activation and inflammatory responses. Here we demonstrate efficacy of BTK inhibition in a model of secondary progressive autoimmune demyelination in Biozzi mice with experimental autoimmune encephalomyelitis (EAE). We show that late in the course of disease, EAE severity could not be reduced with a potent relapse inhibitor, FTY720 (fingolimod), indicating that disease was relapse-independent. During this same phase of disease, treatment with a BTK inhibitor reduced both EAE severity and demyelination compared to vehicle treatment. Compared to vehicle treatment, late therapeutic BTK inhibition resulted in fewer spinal cord-infiltrating myeloid cells, with lower expression of CD86, pro-IL-1β, CD206, and Iba1, and higher expression of Arg1, in both tissue-resident and infiltrating myeloid cells, suggesting a less inflammatory myeloid cell milieu. These changes were accompanied by decreased spinal cord axonal damage. We show similar efficacy with two small molecule inhibitors, including a novel, highly selective, central nervous system-penetrant BTK inhibitor, GB7208. These results suggest that through lymphoid and myeloid cell regulation, BTK inhibition reduced neurodegeneration and disease progression during secondary progressive EAE. |
| first_indexed | 2024-03-12T23:20:21Z |
| format | Article |
| id | doaj.art-74c8df65a413425fbb6a1380a390fcf6 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-03-12T23:20:21Z |
| publishDate | 2023-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-74c8df65a413425fbb6a1380a390fcf62023-07-16T11:31:05ZengBMCActa Neuropathologica Communications2051-59602023-07-0111111910.1186/s40478-023-01614-wBruton’s tyrosine kinase inhibition reduces disease severity in a model of secondary progressive autoimmune demyelinationKirsten Scarlett Evonuk0Sen Wang1Josh Mattie2C. J. Cracchiolo3Reine Mager4Željko Ferenčić5Ethan Sprague6Brandon Carrier7Kai Schofield8Evelyn Martinez9Zachary Stewart10Tara Petrosino11Gregory Andrew Johnson12Isharat Yusuf13Warren Plaisted14Zachary Naiman15Timothy Delp16Laura Carter17Suzana Marušić18Hooke Laboratories, LLCHooke Laboratories, LLCHooke Laboratories, LLCHooke Laboratories, LLCHooke Laboratories, LLCHooke Laboratories, LLCHooke Laboratories, LLCHooke Laboratories, LLCHooke Laboratories, LLCHooke Laboratories, LLCHooke Laboratories, LLCHooke Laboratories, LLCHooke Laboratories, LLCGossamer BioGossamer BioGossamer BioHooke Laboratories, LLCGossamer BioHooke Laboratories, LLCAbstract Bruton’s tyrosine kinase (BTK) is an emerging target in multiple sclerosis (MS). Alongside its role in B cell receptor signaling and B cell development, BTK regulates myeloid cell activation and inflammatory responses. Here we demonstrate efficacy of BTK inhibition in a model of secondary progressive autoimmune demyelination in Biozzi mice with experimental autoimmune encephalomyelitis (EAE). We show that late in the course of disease, EAE severity could not be reduced with a potent relapse inhibitor, FTY720 (fingolimod), indicating that disease was relapse-independent. During this same phase of disease, treatment with a BTK inhibitor reduced both EAE severity and demyelination compared to vehicle treatment. Compared to vehicle treatment, late therapeutic BTK inhibition resulted in fewer spinal cord-infiltrating myeloid cells, with lower expression of CD86, pro-IL-1β, CD206, and Iba1, and higher expression of Arg1, in both tissue-resident and infiltrating myeloid cells, suggesting a less inflammatory myeloid cell milieu. These changes were accompanied by decreased spinal cord axonal damage. We show similar efficacy with two small molecule inhibitors, including a novel, highly selective, central nervous system-penetrant BTK inhibitor, GB7208. These results suggest that through lymphoid and myeloid cell regulation, BTK inhibition reduced neurodegeneration and disease progression during secondary progressive EAE.https://doi.org/10.1186/s40478-023-01614-wMultiple sclerosisSecondary progressiveDemyelinationMicrogliaB cellsMyeloid cells |
| spellingShingle | Kirsten Scarlett Evonuk Sen Wang Josh Mattie C. J. Cracchiolo Reine Mager Željko Ferenčić Ethan Sprague Brandon Carrier Kai Schofield Evelyn Martinez Zachary Stewart Tara Petrosino Gregory Andrew Johnson Isharat Yusuf Warren Plaisted Zachary Naiman Timothy Delp Laura Carter Suzana Marušić Bruton’s tyrosine kinase inhibition reduces disease severity in a model of secondary progressive autoimmune demyelination Acta Neuropathologica Communications Multiple sclerosis Secondary progressive Demyelination Microglia B cells Myeloid cells |
| title | Bruton’s tyrosine kinase inhibition reduces disease severity in a model of secondary progressive autoimmune demyelination |
| title_full | Bruton’s tyrosine kinase inhibition reduces disease severity in a model of secondary progressive autoimmune demyelination |
| title_fullStr | Bruton’s tyrosine kinase inhibition reduces disease severity in a model of secondary progressive autoimmune demyelination |
| title_full_unstemmed | Bruton’s tyrosine kinase inhibition reduces disease severity in a model of secondary progressive autoimmune demyelination |
| title_short | Bruton’s tyrosine kinase inhibition reduces disease severity in a model of secondary progressive autoimmune demyelination |
| title_sort | bruton s tyrosine kinase inhibition reduces disease severity in a model of secondary progressive autoimmune demyelination |
| topic | Multiple sclerosis Secondary progressive Demyelination Microglia B cells Myeloid cells |
| url | https://doi.org/10.1186/s40478-023-01614-w |
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