High-mobility group box 1 is an important mediator of microglial activation
induced by cortical spreading depression
#MMPMID27142867
Takizawa T
; Shibata M
; Kayama Y
; Shimizu T
; Toriumi H
; Ebine T
; Unekawa M
; Koh A
; Yoshimura A
; Suzuki N
J Cereb Blood Flow Metab
2017[Mar]; 37
(3
): 890-901
PMID27142867
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Single episodes of cortical spreading depression (CSD) are believed to cause
typical migraine aura, whereas clusters of spreading depolarizations have been
observed in cerebral ischemia and subarachnoid hemorrhage. We recently
demonstrated that the release of high-mobility group box 1 (HMGB1) from cortical
neurons after CSD in a rodent model is dependent on the number of CSD episodes,
such that only multiple CSD episodes can induce significant HMGB1 release. Here,
we report that only multiple CSD inductions caused microglial hypertrophy
(activation) accompanied by a greater impact on the transcription activity of the
HMGB1 receptor genes, TLR2 and TLR4, while the total number of cortical microglia
was not affected. Both an HMGB1-neurtalizing antibody and the HMGB1 inhibitor
glycyrrhizin abrogated multiple CSD-induced microglial hypertrophy. Moreover,
multiple CSD inductions failed to induce microglial hypertrophy in TLR2/4 double
knockout mice. These results strongly implicate the HMGB1-TLR2/4 axis in the
activation of microglia following multiple CSD inductions. Increased expression
of the lysosomal acid hydrolase cathepsin D was detected in activated microglia
by immunostaining, suggesting that lysosomal phagocytic activity may be enhanced
in multiple CSD-activated microglia.
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