Genetic targeting of protease activated receptor 2 reduces inflammatory astrogliosis and improves recovery of function after spinal cord injury
Inflammatory-astrogliosis exacerbates damage in the injured spinal cord and limits repair. Here we identify Protease Activated Receptor 2 (PAR2) as an essential regulator of these events with mice lacking the PAR2 gene showing greater improvements in motor coordination and strength after compression...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2015-11-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996115300413 |
| _version_ | 1818651554302918656 |
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| author | Maja Radulovic Hyesook Yoon Jianmin Wu Karim Mustafa Michael G. Fehlings Isobel A. Scarisbrick |
| author_facet | Maja Radulovic Hyesook Yoon Jianmin Wu Karim Mustafa Michael G. Fehlings Isobel A. Scarisbrick |
| author_sort | Maja Radulovic |
| collection | DOAJ |
| description | Inflammatory-astrogliosis exacerbates damage in the injured spinal cord and limits repair. Here we identify Protease Activated Receptor 2 (PAR2) as an essential regulator of these events with mice lacking the PAR2 gene showing greater improvements in motor coordination and strength after compression-spinal cord injury (SCI) compared to wild type littermates. Molecular profiling of the injury epicenter, and spinal segments above and below, demonstrated that mice lacking PAR2 had significantly attenuated elevations in key hallmarks of astrogliosis (glial fibrillary acidic protein (GFAP), vimentin and neurocan) and in expression of pro-inflammatory cytokines (interleukin-6 (IL-6), tumor necrosis factor (TNF) and interleukin-1 beta (IL-1β)). SCI in PAR2−/− mice was also accompanied by improved preservation of protein kinase C gamma (PKCγ)-immunopositive corticospinal axons and reductions in GFAP-immunoreactivity, expression of the pro-apoptotic marker BCL2-interacting mediator of cell death (BIM), and in signal transducer and activator of transcription 3 (STAT3). The potential mechanistic link between PAR2, STAT3 and astrogliosis was further investigated in primary astrocytes to reveal that the SCI-related serine protease, neurosin (kallikrein 6) promotes IL-6 secretion in a PAR2 and STAT3-dependent manner. Data point to a signaling circuit in primary astrocytes in which neurosin signaling at PAR2 promotes IL-6 secretion and canonical STAT3 signaling. IL-6 promotes expression of GFAP, vimentin, additional IL-6 and robust increases in both neurosin and PAR2, thereby driving the PAR2-signaling circuit forward. Given the significant reductions in astrogliosis and inflammation as well as superior neuromotor recovery observed in PAR2 knockout mice after SCI, we suggest that this receptor and its agonists represent new drug targets to foster neuromotor recovery. |
| first_indexed | 2024-12-17T02:07:57Z |
| format | Article |
| id | doaj.art-d47a062d20944b5b81bbc841abda47c0 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T02:07:57Z |
| publishDate | 2015-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-d47a062d20944b5b81bbc841abda47c02022-12-21T22:07:38ZengElsevierNeurobiology of Disease1095-953X2015-11-01837589Genetic targeting of protease activated receptor 2 reduces inflammatory astrogliosis and improves recovery of function after spinal cord injuryMaja Radulovic0Hyesook Yoon1Jianmin Wu2Karim Mustafa3Michael G. Fehlings4Isobel A. Scarisbrick5Neurobiology of Disease Program, Mayo Medical and Graduate School, Rehabilitation Medicine Research Center, Rochester, MN 55905, United StatesDepartment of Physical Medicine and Rehabilitation, Mayo Medical and Graduate School, Rehabilitation Medicine Research Center, Rochester, MN 55905, United States; Department of Physiology and Biomedical Engineering, Mayo Medical and Graduate School, Rehabilitation Medicine Research Center, Rochester, MN 55905, United StatesDepartment of Physical Medicine and Rehabilitation, Mayo Medical and Graduate School, Rehabilitation Medicine Research Center, Rochester, MN 55905, United StatesNeurobiology of Disease Program, Mayo Medical and Graduate School, Rehabilitation Medicine Research Center, Rochester, MN 55905, United StatesDepartment of Surgery, Toronto Western Research Institute, Toronto, ON M5T 2S8, CanadaNeurobiology of Disease Program, Mayo Medical and Graduate School, Rehabilitation Medicine Research Center, Rochester, MN 55905, United States; Department of Physical Medicine and Rehabilitation, Mayo Medical and Graduate School, Rehabilitation Medicine Research Center, Rochester, MN 55905, United States; Department of Physiology and Biomedical Engineering, Mayo Medical and Graduate School, Rehabilitation Medicine Research Center, Rochester, MN 55905, United States; Corresponding author at: Neurobiology of Disease Program, 642B Guggenheim Building, Mayo Clinic Rochester, 200 First St., SW., Rochester, MN 55905, United States.Inflammatory-astrogliosis exacerbates damage in the injured spinal cord and limits repair. Here we identify Protease Activated Receptor 2 (PAR2) as an essential regulator of these events with mice lacking the PAR2 gene showing greater improvements in motor coordination and strength after compression-spinal cord injury (SCI) compared to wild type littermates. Molecular profiling of the injury epicenter, and spinal segments above and below, demonstrated that mice lacking PAR2 had significantly attenuated elevations in key hallmarks of astrogliosis (glial fibrillary acidic protein (GFAP), vimentin and neurocan) and in expression of pro-inflammatory cytokines (interleukin-6 (IL-6), tumor necrosis factor (TNF) and interleukin-1 beta (IL-1β)). SCI in PAR2−/− mice was also accompanied by improved preservation of protein kinase C gamma (PKCγ)-immunopositive corticospinal axons and reductions in GFAP-immunoreactivity, expression of the pro-apoptotic marker BCL2-interacting mediator of cell death (BIM), and in signal transducer and activator of transcription 3 (STAT3). The potential mechanistic link between PAR2, STAT3 and astrogliosis was further investigated in primary astrocytes to reveal that the SCI-related serine protease, neurosin (kallikrein 6) promotes IL-6 secretion in a PAR2 and STAT3-dependent manner. Data point to a signaling circuit in primary astrocytes in which neurosin signaling at PAR2 promotes IL-6 secretion and canonical STAT3 signaling. IL-6 promotes expression of GFAP, vimentin, additional IL-6 and robust increases in both neurosin and PAR2, thereby driving the PAR2-signaling circuit forward. Given the significant reductions in astrogliosis and inflammation as well as superior neuromotor recovery observed in PAR2 knockout mice after SCI, we suggest that this receptor and its agonists represent new drug targets to foster neuromotor recovery.http://www.sciencedirect.com/science/article/pii/S0969996115300413Traumatic spinal cord injuryAstrogliosisInflammationCytokineGPCRSerine protease |
| spellingShingle | Maja Radulovic Hyesook Yoon Jianmin Wu Karim Mustafa Michael G. Fehlings Isobel A. Scarisbrick Genetic targeting of protease activated receptor 2 reduces inflammatory astrogliosis and improves recovery of function after spinal cord injury Neurobiology of Disease Traumatic spinal cord injury Astrogliosis Inflammation Cytokine GPCR Serine protease |
| title | Genetic targeting of protease activated receptor 2 reduces inflammatory astrogliosis and improves recovery of function after spinal cord injury |
| title_full | Genetic targeting of protease activated receptor 2 reduces inflammatory astrogliosis and improves recovery of function after spinal cord injury |
| title_fullStr | Genetic targeting of protease activated receptor 2 reduces inflammatory astrogliosis and improves recovery of function after spinal cord injury |
| title_full_unstemmed | Genetic targeting of protease activated receptor 2 reduces inflammatory astrogliosis and improves recovery of function after spinal cord injury |
| title_short | Genetic targeting of protease activated receptor 2 reduces inflammatory astrogliosis and improves recovery of function after spinal cord injury |
| title_sort | genetic targeting of protease activated receptor 2 reduces inflammatory astrogliosis and improves recovery of function after spinal cord injury |
| topic | Traumatic spinal cord injury Astrogliosis Inflammation Cytokine GPCR Serine protease |
| url | http://www.sciencedirect.com/science/article/pii/S0969996115300413 |
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