title: Genetic targeting of protease activated receptor 2 reduces inflammatory astrogliosis and improves recovery of function after spinal cord injury.
abstract: 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.
authors: Neurobiology of Disease Program, Mayo Medical and Graduate School, Rehabilitation Medicine Research Center, Rochester, MN 55905, United States.
authors: Maja
authors: M
authors: Radulovic
authors: 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.
authors: Hyesook
authors: H
authors: Yoon
authors: Department of Physical Medicine and Rehabilitation, Mayo Medical and Graduate School, Rehabilitation Medicine Research Center, Rochester, MN 55905, United States.
authors: Jianmin
authors: J
authors: Wu
authors: Neurobiology of Disease Program, Mayo Medical and Graduate School, Rehabilitation Medicine Research Center, Rochester, MN 55905, United States.
authors: Karim
authors: K
authors: Mustafa
authors: Department of Surgery, Toronto Western Research Institute, Toronto, ON M5T 2S8, Canada.
authors: Michael G
authors: MG
authors: Fehlings
authors: Neurobiology 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. Electronic address: Scarisbrick.Isobel@mayo.edu.
authors: Isobel A
authors: IA
authors: Scarisbrick
mesh_terms: D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001369:Axons / Q000378:metabolism / Q000473:pathology; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007610:Kallikreins / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D009187:Myelitis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism; D011712:Pyramidal Tracts / Q000378:metabolism / Q000473:pathology; D044464:Receptor, PAR-2 / Q000235:genetics / Q000378:metabolism*; D020127:Recovery of Function; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013119:Spinal Cord Injuries / Q000150:complications / Q000378:metabolism* / Q000473:pathology
chemical_list: D018836:Inflammation Mediators; D015850:Interleukin-6; D044464:Receptor, PAR-2; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C087857:protein kinase C gamma; D011493:Protein Kinase C; D007610:Kallikreins; C491223:Prss18 protein, mouse
keywords: Astrogliosis; Cytokine; GPCR; Inflammation; Serine protease; Traumatic spinal cord injury