Genetic targeting of protease activated receptor 2 reduces inflammatory astrogliosis and improves recovery of function after spinal cord injury

Maja Radulovic, Hyesook Yoon, Jianmin Wu, Karim Mustafa, Michael G. Fehlings, Isobel A Scarisbrick

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
Article number3587
Pages (from-to)75-89
Number of pages15
JournalNeurobiology of Disease
Volume83
DOIs
StatePublished - Nov 1 2015

Fingerprint

PAR-2 Receptor
Recovery of Function
Spinal Cord Injuries
STAT3 Transcription Factor
Interleukin-6
Glial Fibrillary Acidic Protein
Vimentin
Astrocytes
Neurocan
Spinal Cord Regeneration
Spinal Injuries
Kallikreins
Serine Proteases
Interleukin-1beta
Knockout Mice
Axons
Cell Death
Tumor Necrosis Factor-alpha

Keywords

  • Astrogliosis
  • Cytokine
  • GPCR
  • Inflammation
  • Serine protease
  • Traumatic spinal cord injury

ASJC Scopus subject areas

  • Neurology

Cite this

Genetic targeting of protease activated receptor 2 reduces inflammatory astrogliosis and improves recovery of function after spinal cord injury. / Radulovic, Maja; Yoon, Hyesook; Wu, Jianmin; Mustafa, Karim; Fehlings, Michael G.; Scarisbrick, Isobel A.

In: Neurobiology of Disease, Vol. 83, 3587, 01.11.2015, p. 75-89.

Research output: Contribution to journalArticle

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