Role of kallikrein 6‐mediated PAR signaling in astrogliosis

Abstract

A remarkable feature of the expression of kallikrein 6 (KLK6) in the CNS is its abundance in oligodendroglia and neurons, but relative lack of expression in astrocytes. We have shown in cases of CNS injury however, that KLK6 is induced in reactive astrocytes and exhibits prolonged expression in astroglial scar tissue in cases of spinal cord injury, multiple sclerosis and glioblastoma multiforme. In this study, we address the hypothesis that KLK6 plays a role in the promotion of astrogliosis and that this occurs by selective activation of protease activated receptors (PARs). Using primary murine astrocytes we show KLK6 promotes rapid transformation from an epithelioid to a stellate morphology and secretion of interleukin 6, each a hallmark of astrogliosis. The ability of KLK6 to promote stellation was shown to occur as early as 4 hours after a single pulse of KLK6, to be dose‐dependent, and to require activation of PKC and AKT signaling cascades. The stellation promoting activities of KLK6 were further shown to depend at least in part on activation of the thrombin receptor PAR1, since these effects were reduced in astrocytes derived from PAR1‐deficient mice and by a PAR1 specific inhibitor, SCH79797. These results point to novel roles for KLK6‐mediated PAR signaling in the spectrum of events that culminate in astrogliosis. This work was supported by NIH R01 NS052741.