CD200-CD200R1 inhibitory signaling prevents spontaneous bacterial infection and promotes resolution of neuroinflammation and recovery after stroke
Abstract Background Ischemic stroke results in a robust inflammatory response within the central nervous system. As the immune-inhibitory CD200-CD200 receptor 1 (CD200R1) signaling axis is a known regulator of immune homeostasis, we hypothesized that it may play a role in post-stroke immune suppress...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2019-02-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-019-1426-3 |
| _version_ | 1818020454598705152 |
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| author | Rodney M. Ritzel Abdullah Al Mamun Joshua Crapser Rajkumar Verma Anita R. Patel Brittany E. Knight Nia Harris Nickolas Mancini Meaghan Roy-O’Reilly Bhanu Priya Ganesh Fudong Liu Louise D. McCullough |
| author_facet | Rodney M. Ritzel Abdullah Al Mamun Joshua Crapser Rajkumar Verma Anita R. Patel Brittany E. Knight Nia Harris Nickolas Mancini Meaghan Roy-O’Reilly Bhanu Priya Ganesh Fudong Liu Louise D. McCullough |
| author_sort | Rodney M. Ritzel |
| collection | DOAJ |
| description | Abstract Background Ischemic stroke results in a robust inflammatory response within the central nervous system. As the immune-inhibitory CD200-CD200 receptor 1 (CD200R1) signaling axis is a known regulator of immune homeostasis, we hypothesized that it may play a role in post-stroke immune suppression after stroke. Methods In this study, we investigated the role of CD200R1-mediated signaling in stroke using CD200 receptor 1-deficient mice. Mice were subjected to a 60-min middle cerebral artery occlusion and evaluated at days 3 and 7, representing the respective peak and early resolution stages of neuroinflammation in this model of ischemic stroke. Infarct size and behavioral deficits were assessed at both time points. Central and peripheral cellular immune responses were measured using flow cytometry. Bacterial colonization was determined in lung tissue homogenates both after acute stroke and in an LPS model of systemic inflammation. Results In wild-type (WT) animals, CD200R1 was expressed on infiltrating monocytes and lymphocytes after stroke but was absent on microglia. Early after ischemia (72 h), CD200R1-knockout (KO) mice had significantly poorer survival rates and an enhanced susceptibility to spontaneous bacterial colonization of the respiratory tract compared to wild-type (WT) controls, despite no difference in infarct or neurological deficits. While the CNS inflammation was resolved by day 7 post-stroke in WT mice, brain-resident microglia and monocyte activation persisted in CD200R1-KO mice, accompanied by a delayed, augmented lymphocyte response. At this time point, CD200R1-KO mice displayed greater weight loss, more severe neurological deficits, and impaired motor function compared to WT. Systemically, CD200R1-KO mice exhibited signs of persistent infection including lymphopenia, T cell activation and memory conversion, and narrowing of the TCR repertoire. These findings were confirmed in a second model of acute neuroinflammation induced by systemic endotoxin challenge. Conclusion This study defines an essential role of CD200-CD200R1 signaling in stroke. Loss of CD200R1 led to high mortality, increased rates of post-stroke infection, and enhanced entry of peripheral leukocytes into the brain after ischemia, with no increase in infarct size. This suggests that the loss of CD200 receptor leads to enhanced peripheral inflammation that is triggered by brain injury. |
| first_indexed | 2024-04-14T08:05:34Z |
| format | Article |
| id | doaj.art-bd41130a382a4de5a03d5632a95c4100 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-14T08:05:34Z |
| publishDate | 2019-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-bd41130a382a4de5a03d5632a95c41002022-12-22T02:04:46ZengBMCJournal of Neuroinflammation1742-20942019-02-0116111610.1186/s12974-019-1426-3CD200-CD200R1 inhibitory signaling prevents spontaneous bacterial infection and promotes resolution of neuroinflammation and recovery after strokeRodney M. Ritzel0Abdullah Al Mamun1Joshua Crapser2Rajkumar Verma3Anita R. Patel4Brittany E. Knight5Nia Harris6Nickolas Mancini7Meaghan Roy-O’Reilly8Bhanu Priya Ganesh9Fudong Liu10Louise D. McCullough11Department of Anesthesiology, Center for Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of MedicineDepartment of Neurology, McGovern Medical School, University of Texas Health Science CenterNeuroscience Department, University of Connecticut Health CenterNeuroscience Department, University of Connecticut Health CenterNeuroscience Department, University of Connecticut Health CenterNeuroscience Department, University of Connecticut Health CenterNeuroscience Department, University of Connecticut Health CenterNeuroscience Department, University of Connecticut Health CenterDepartment of Neurology, McGovern Medical School, University of Texas Health Science CenterDepartment of Neurology, McGovern Medical School, University of Texas Health Science CenterDepartment of Neurology, McGovern Medical School, University of Texas Health Science CenterDepartment of Neurology, McGovern Medical School, University of Texas Health Science CenterAbstract Background Ischemic stroke results in a robust inflammatory response within the central nervous system. As the immune-inhibitory CD200-CD200 receptor 1 (CD200R1) signaling axis is a known regulator of immune homeostasis, we hypothesized that it may play a role in post-stroke immune suppression after stroke. Methods In this study, we investigated the role of CD200R1-mediated signaling in stroke using CD200 receptor 1-deficient mice. Mice were subjected to a 60-min middle cerebral artery occlusion and evaluated at days 3 and 7, representing the respective peak and early resolution stages of neuroinflammation in this model of ischemic stroke. Infarct size and behavioral deficits were assessed at both time points. Central and peripheral cellular immune responses were measured using flow cytometry. Bacterial colonization was determined in lung tissue homogenates both after acute stroke and in an LPS model of systemic inflammation. Results In wild-type (WT) animals, CD200R1 was expressed on infiltrating monocytes and lymphocytes after stroke but was absent on microglia. Early after ischemia (72 h), CD200R1-knockout (KO) mice had significantly poorer survival rates and an enhanced susceptibility to spontaneous bacterial colonization of the respiratory tract compared to wild-type (WT) controls, despite no difference in infarct or neurological deficits. While the CNS inflammation was resolved by day 7 post-stroke in WT mice, brain-resident microglia and monocyte activation persisted in CD200R1-KO mice, accompanied by a delayed, augmented lymphocyte response. At this time point, CD200R1-KO mice displayed greater weight loss, more severe neurological deficits, and impaired motor function compared to WT. Systemically, CD200R1-KO mice exhibited signs of persistent infection including lymphopenia, T cell activation and memory conversion, and narrowing of the TCR repertoire. These findings were confirmed in a second model of acute neuroinflammation induced by systemic endotoxin challenge. Conclusion This study defines an essential role of CD200-CD200R1 signaling in stroke. Loss of CD200R1 led to high mortality, increased rates of post-stroke infection, and enhanced entry of peripheral leukocytes into the brain after ischemia, with no increase in infarct size. This suggests that the loss of CD200 receptor leads to enhanced peripheral inflammation that is triggered by brain injury.http://link.springer.com/article/10.1186/s12974-019-1426-3CD200R1MicrogliaIschemic strokeImmunosuppression |
| spellingShingle | Rodney M. Ritzel Abdullah Al Mamun Joshua Crapser Rajkumar Verma Anita R. Patel Brittany E. Knight Nia Harris Nickolas Mancini Meaghan Roy-O’Reilly Bhanu Priya Ganesh Fudong Liu Louise D. McCullough CD200-CD200R1 inhibitory signaling prevents spontaneous bacterial infection and promotes resolution of neuroinflammation and recovery after stroke Journal of Neuroinflammation CD200R1 Microglia Ischemic stroke Immunosuppression |
| title | CD200-CD200R1 inhibitory signaling prevents spontaneous bacterial infection and promotes resolution of neuroinflammation and recovery after stroke |
| title_full | CD200-CD200R1 inhibitory signaling prevents spontaneous bacterial infection and promotes resolution of neuroinflammation and recovery after stroke |
| title_fullStr | CD200-CD200R1 inhibitory signaling prevents spontaneous bacterial infection and promotes resolution of neuroinflammation and recovery after stroke |
| title_full_unstemmed | CD200-CD200R1 inhibitory signaling prevents spontaneous bacterial infection and promotes resolution of neuroinflammation and recovery after stroke |
| title_short | CD200-CD200R1 inhibitory signaling prevents spontaneous bacterial infection and promotes resolution of neuroinflammation and recovery after stroke |
| title_sort | cd200 cd200r1 inhibitory signaling prevents spontaneous bacterial infection and promotes resolution of neuroinflammation and recovery after stroke |
| topic | CD200R1 Microglia Ischemic stroke Immunosuppression |
| url | http://link.springer.com/article/10.1186/s12974-019-1426-3 |
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