title: Targeting the thrombin receptor modulates inflammation and astrogliosis to improve recovery after spinal cord injury.
abstract: The deregulation of serine protease activity is a common feature of neurological injury, but little is known regarding their mechanisms of action or whether they can be targeted to facilitate repair. In this study we demonstrate that the thrombin receptor (Protease Activated Receptor 1, (PAR1)) serves as a critical translator of the spinal cord injury (SCI) proteolytic microenvironment into a cascade of pro-inflammatory events that contribute to astrogliosis and functional decline. PAR1 knockout mice displayed improved locomotor recovery after SCI and reduced signatures of inflammation and astrogliosis, including expression of glial fibrillary acidic protein (GFAP), vimentin, and STAT3 signaling. SCI-associated elevations in pro-inflammatory cytokines such as IL-1β and IL-6 were also reduced in PAR1-/- mice and co-ordinate improvements in tissue sparing and preservation of NeuN-positive ventral horn neurons, and PKCγ corticospinal axons, were observed. PAR1 and its agonist's thrombin and neurosin were expressed by perilesional astrocytes and each agonist increased the production of IL-6 and STAT3 signaling in primary astrocyte cultures in a PAR1-dependent manner. In turn, IL-6-stimulated astrocytes increased expression of PAR1, thrombin, and neurosin, pointing to a model in which PAR1 activation contributes to increased astrogliosis by feedforward- and feedback-signaling dynamics. Collectively, these findings identify the thrombin receptor as a key mediator of inflammation and astrogliosis in the aftermath of SCI that can be targeted to reduce neurodegeneration and improve neurobehavioral recovery.
authors.affiliation: Neurobiology of Disease Program, Mayo Medical and Graduate School, Rehabilitation Medicine Research Center, Rochester 55905, MN, United States.
authors.forename: Maja
authors.initials: M
authors.lastname: Radulovic
authors.affiliation: 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.forename: Hyesook
authors.initials: H
authors.lastname: Yoon
authors.affiliation: Department of Physical Medicine and Rehabilitation, Mayo Medical and Graduate School, Rehabilitation Medicine Research Center, Rochester, MN 55905, United States.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wu
authors.affiliation: Neurobiology of Disease Program, Mayo Medical and Graduate School, Rehabilitation Medicine Research Center, Rochester 55905, MN, United States.
authors.forename: Karim
authors.initials: K
authors.lastname: Mustafa
authors.affiliation: Neurobiology of Disease Program, Mayo Medical and Graduate School, Rehabilitation Medicine Research Center, Rochester 55905, MN, 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.forename: Isobel A
authors.initials: IA
authors.lastname: Scarisbrick
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001369:Axons / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000378:metabolism / Q000473:pathology*; D007249:Inflammation / Q000378:metabolism; D008822:Mice, Transgenic; D018179:Receptors, Thrombin / Q000378:metabolism*; D020127:Recovery of Function / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D018179:Receptors, Thrombin
keywords: Astrocyte; Astrogliosis; Cytokine; GPCR; Inflammation; Interleukin 6; Microglia; Serine protease; Traumatic spinal cord injury