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Participation of protease‐activated receptor‐1 in thrombin‐induced microglial activation
Author(s) -
Suo Zhiming,
Wu Min,
Ameenuddin Syed,
Anderson Heidi E.,
Zoloty Jamie E.,
Citron Bruce A.,
AndradeGordon Patricia,
Festoff Barry W.
Publication year - 2002
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.0022-3042.2001.00745.x
Subject(s) - thrombin , microglia , microbiology and biotechnology , protease activated receptor , receptor , p38 mitogen activated protein kinases , protease activated receptor 2 , tumor necrosis factor alpha , inflammation , chemistry , biology , signal transduction , mapk/erk pathway , immunology , biochemistry , platelet , enzyme linked receptor
Abstract Activation of microglia, the resident macrophages in the CNS, plays a significant role in neuronal death or degeneration in a broad spectrum of CNS disorders. Recent studies indicate that nanomolar concentrations of the serine protease, thrombin, can activate microglia in culture. However, in contrast to other neural cells responsive to thrombin, the participation of novel protease‐activated receptors (PARs), such as the prototypic thrombin receptor PAR1, in thrombin‐induced microglial activation was cast in doubt. In this report, by utilizing primary microglial cultures from PAR1 knockout (PAR1–/–) mice, application of the PAR1 active peptide TRAP‐6 (SFLLRN) in comparison to a scrambled peptide (LFLNR), we have unambiguously demonstrated that murine microglia constitutively express PAR1 mRNA that is translated into fully functional protein. Activation of the microglial PAR1 induces a rapid cytosolic free [Ca 2+ ] i increase and transient activation of both p38 and p44/42 mitogen‐activated protein kinases. Moreover, although in part, this PAR1 activation directly contributes to thrombin‐induced microglial proliferation. Furthermore, although not directly inducing tumor necrosis factor‐α (TNF‐α) release, PAR1 activation up‐regulates microglial CD40 expression and potentiates CD40 ligand‐induced TNF‐α production, thus indirectly contributing to microglial activation. Taken together, these results demonstrate an essential role of PAR1 in thrombin‐induced microglial activation. In addition, strategies aimed at blocking thrombin signaling through PAR1 may be therapeutically valuable for diseases associated with cerebral vascular damage and significant inflammation with microglial activation.