CXCL13 expressed on inflamed cerebral blood vessels recruit IL-21 producing TFH cells to damage neurons following stroke
Abstract Background Ischemic stroke is a leading cause of mortality worldwide, largely due to the inflammatory response to brain ischemia during post-stroke reperfusion. Despite ongoing intensive research, there have not been any clinically approved drugs targeting the inflammatory component to stro...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-05-01
|
| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-022-02490-2 |
| _version_ | 1811258687765872640 |
|---|---|
| author | Aditya Rayasam Julie A. Kijak Lee Kissel Yun Hwa Choi Taehee Kim Martin Hsu Dinesh Joshi Collin J. Laaker Peter Cismaru Anders Lindstedt Krisztian Kovacs Raghu Vemuganti Shing Yan Chiu Thanthrige Thiunuwan Priyathilaka Matyas Sandor Zsuzsanna Fabry |
| author_facet | Aditya Rayasam Julie A. Kijak Lee Kissel Yun Hwa Choi Taehee Kim Martin Hsu Dinesh Joshi Collin J. Laaker Peter Cismaru Anders Lindstedt Krisztian Kovacs Raghu Vemuganti Shing Yan Chiu Thanthrige Thiunuwan Priyathilaka Matyas Sandor Zsuzsanna Fabry |
| author_sort | Aditya Rayasam |
| collection | DOAJ |
| description | Abstract Background Ischemic stroke is a leading cause of mortality worldwide, largely due to the inflammatory response to brain ischemia during post-stroke reperfusion. Despite ongoing intensive research, there have not been any clinically approved drugs targeting the inflammatory component to stroke. Preclinical studies have identified T cells as pro-inflammatory mediators of ischemic brain damage, yet mechanisms that regulate the infiltration and phenotype of these cells are lacking. Further understanding of how T cells migrate to the ischemic brain and facilitate neuronal death during brain ischemia can reveal novel targets for post-stroke intervention. Methods To identify the population of T cells that produce IL-21 and contribute to stroke, we performed transient middle cerebral artery occlusion (tMCAO) in mice and performed flow cytometry on brain tissue. We also utilized immunohistochemistry in both mouse and human brain sections to identify cell types and inflammatory mediators related to stroke-induced IL-21 signaling. To mechanistically demonstrate our findings, we employed pharmacological inhibitor anti-CXCL13 and performed histological analyses to evaluate its effects on brain infarct damage. Finally, to evaluate cellular mechanisms of stroke, we exposed mouse primary neurons to oxygen glucose deprivation (OGD) conditions with or without IL-21 and measured cell viability, caspase activity and JAK/STAT signaling. Results Flow cytometry on brains from mice following tMCAO identified a novel population of cells IL-21 producing CXCR5+ CD4+ ICOS-1+ T follicular helper cells (TFH) in the ischemic brain early after injury. We observed augmented expression of CXCL13 on inflamed brain vascular cells and demonstrated that inhibition of CXCL13 protects mice from tMCAO by restricting the migration and influence of IL-21 producing TFH cells in the ischemic brain. We also illustrate that neurons express IL-21R in the peri-infarct regions of both mice and human stroke tissue in vivo. Lastly, we found that IL-21 acts on mouse primary ischemic neurons to activate the JAK/STAT pathway and induce caspase 3/7-mediated apoptosis in vitro. Conclusion These findings identify a novel mechanism for how pro-inflammatory T cells are recruited to the ischemic brain to propagate stroke damage and provide a potential new therapeutic target for stroke. |
| first_indexed | 2024-04-12T18:18:19Z |
| format | Article |
| id | doaj.art-e710bc3210a84704b042530e01331994 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-12T18:18:19Z |
| publishDate | 2022-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-e710bc3210a84704b042530e013319942022-12-22T03:21:32ZengBMCJournal of Neuroinflammation1742-20942022-05-0119111510.1186/s12974-022-02490-2CXCL13 expressed on inflamed cerebral blood vessels recruit IL-21 producing TFH cells to damage neurons following strokeAditya Rayasam0Julie A. Kijak1Lee Kissel2Yun Hwa Choi3Taehee Kim4Martin Hsu5Dinesh Joshi6Collin J. Laaker7Peter Cismaru8Anders Lindstedt9Krisztian Kovacs10Raghu Vemuganti11Shing Yan Chiu12Thanthrige Thiunuwan Priyathilaka13Matyas Sandor14Zsuzsanna Fabry15Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-MadisonDepartment of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-MadisonDepartment of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-MadisonDepartment of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-MadisonNeuroscience Training Program, University of Wisconsin-MadisonDepartment of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-MadisonDepartment of Physiology, University of Wisconsin School of MedicineDepartment of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-MadisonDepartment of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-MadisonDepartment of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-MadisonDepartment of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-MadisonNeuroscience Training Program, University of Wisconsin-MadisonNeuroscience Training Program, University of Wisconsin-MadisonDepartment of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-MadisonDepartment of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-MadisonDepartment of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-MadisonAbstract Background Ischemic stroke is a leading cause of mortality worldwide, largely due to the inflammatory response to brain ischemia during post-stroke reperfusion. Despite ongoing intensive research, there have not been any clinically approved drugs targeting the inflammatory component to stroke. Preclinical studies have identified T cells as pro-inflammatory mediators of ischemic brain damage, yet mechanisms that regulate the infiltration and phenotype of these cells are lacking. Further understanding of how T cells migrate to the ischemic brain and facilitate neuronal death during brain ischemia can reveal novel targets for post-stroke intervention. Methods To identify the population of T cells that produce IL-21 and contribute to stroke, we performed transient middle cerebral artery occlusion (tMCAO) in mice and performed flow cytometry on brain tissue. We also utilized immunohistochemistry in both mouse and human brain sections to identify cell types and inflammatory mediators related to stroke-induced IL-21 signaling. To mechanistically demonstrate our findings, we employed pharmacological inhibitor anti-CXCL13 and performed histological analyses to evaluate its effects on brain infarct damage. Finally, to evaluate cellular mechanisms of stroke, we exposed mouse primary neurons to oxygen glucose deprivation (OGD) conditions with or without IL-21 and measured cell viability, caspase activity and JAK/STAT signaling. Results Flow cytometry on brains from mice following tMCAO identified a novel population of cells IL-21 producing CXCR5+ CD4+ ICOS-1+ T follicular helper cells (TFH) in the ischemic brain early after injury. We observed augmented expression of CXCL13 on inflamed brain vascular cells and demonstrated that inhibition of CXCL13 protects mice from tMCAO by restricting the migration and influence of IL-21 producing TFH cells in the ischemic brain. We also illustrate that neurons express IL-21R in the peri-infarct regions of both mice and human stroke tissue in vivo. Lastly, we found that IL-21 acts on mouse primary ischemic neurons to activate the JAK/STAT pathway and induce caspase 3/7-mediated apoptosis in vitro. Conclusion These findings identify a novel mechanism for how pro-inflammatory T cells are recruited to the ischemic brain to propagate stroke damage and provide a potential new therapeutic target for stroke.https://doi.org/10.1186/s12974-022-02490-2LymphocytesNeuroinflammationStrokeImmuneBrainIL-21 |
| spellingShingle | Aditya Rayasam Julie A. Kijak Lee Kissel Yun Hwa Choi Taehee Kim Martin Hsu Dinesh Joshi Collin J. Laaker Peter Cismaru Anders Lindstedt Krisztian Kovacs Raghu Vemuganti Shing Yan Chiu Thanthrige Thiunuwan Priyathilaka Matyas Sandor Zsuzsanna Fabry CXCL13 expressed on inflamed cerebral blood vessels recruit IL-21 producing TFH cells to damage neurons following stroke Journal of Neuroinflammation Lymphocytes Neuroinflammation Stroke Immune Brain IL-21 |
| title | CXCL13 expressed on inflamed cerebral blood vessels recruit IL-21 producing TFH cells to damage neurons following stroke |
| title_full | CXCL13 expressed on inflamed cerebral blood vessels recruit IL-21 producing TFH cells to damage neurons following stroke |
| title_fullStr | CXCL13 expressed on inflamed cerebral blood vessels recruit IL-21 producing TFH cells to damage neurons following stroke |
| title_full_unstemmed | CXCL13 expressed on inflamed cerebral blood vessels recruit IL-21 producing TFH cells to damage neurons following stroke |
| title_short | CXCL13 expressed on inflamed cerebral blood vessels recruit IL-21 producing TFH cells to damage neurons following stroke |
| title_sort | cxcl13 expressed on inflamed cerebral blood vessels recruit il 21 producing tfh cells to damage neurons following stroke |
| topic | Lymphocytes Neuroinflammation Stroke Immune Brain IL-21 |
| url | https://doi.org/10.1186/s12974-022-02490-2 |
| work_keys_str_mv | AT adityarayasam cxcl13expressedoninflamedcerebralbloodvesselsrecruitil21producingtfhcellstodamageneuronsfollowingstroke AT julieakijak cxcl13expressedoninflamedcerebralbloodvesselsrecruitil21producingtfhcellstodamageneuronsfollowingstroke AT leekissel cxcl13expressedoninflamedcerebralbloodvesselsrecruitil21producingtfhcellstodamageneuronsfollowingstroke AT yunhwachoi cxcl13expressedoninflamedcerebralbloodvesselsrecruitil21producingtfhcellstodamageneuronsfollowingstroke AT taeheekim cxcl13expressedoninflamedcerebralbloodvesselsrecruitil21producingtfhcellstodamageneuronsfollowingstroke AT martinhsu cxcl13expressedoninflamedcerebralbloodvesselsrecruitil21producingtfhcellstodamageneuronsfollowingstroke AT dineshjoshi cxcl13expressedoninflamedcerebralbloodvesselsrecruitil21producingtfhcellstodamageneuronsfollowingstroke AT collinjlaaker cxcl13expressedoninflamedcerebralbloodvesselsrecruitil21producingtfhcellstodamageneuronsfollowingstroke AT petercismaru cxcl13expressedoninflamedcerebralbloodvesselsrecruitil21producingtfhcellstodamageneuronsfollowingstroke AT anderslindstedt cxcl13expressedoninflamedcerebralbloodvesselsrecruitil21producingtfhcellstodamageneuronsfollowingstroke AT krisztiankovacs cxcl13expressedoninflamedcerebralbloodvesselsrecruitil21producingtfhcellstodamageneuronsfollowingstroke AT raghuvemuganti cxcl13expressedoninflamedcerebralbloodvesselsrecruitil21producingtfhcellstodamageneuronsfollowingstroke AT shingyanchiu cxcl13expressedoninflamedcerebralbloodvesselsrecruitil21producingtfhcellstodamageneuronsfollowingstroke AT thanthrigethiunuwanpriyathilaka cxcl13expressedoninflamedcerebralbloodvesselsrecruitil21producingtfhcellstodamageneuronsfollowingstroke AT matyassandor cxcl13expressedoninflamedcerebralbloodvesselsrecruitil21producingtfhcellstodamageneuronsfollowingstroke AT zsuzsannafabry cxcl13expressedoninflamedcerebralbloodvesselsrecruitil21producingtfhcellstodamageneuronsfollowingstroke |