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PERK-dependent activation of JAK1 and STAT3 contributes to endoplasmic reticulum
stress-induced inflammation
#MMPMID25113558
Meares GP
; Liu Y
; Rajbhandari R
; Qin H
; Nozell SE
; Mobley JA
; Corbett JA
; Benveniste EN
Mol Cell Biol
2014[Oct]; 34
(20
): 3911-25
PMID25113558
show ga
Neuroinflammation and endoplasmic reticulum (ER) stress are associated with many
neurological diseases. Here, we have examined the interaction between ER stress
and JAK/STAT-dependent inflammation in glial cells. We show that ER stress is
present in the central nervous system (CNS) concomitant with inflammation and
astrogliosis in the multiple sclerosis (MS) mouse model of experimental
autoimmune encephalomyelitis (EAE). Astrocytes do not easily succumb to ER stress
but rather activate an inflammatory program involving activation of STAT3 in a
JAK1-dependent fashion. ER stress-induced activation of the JAK1/STAT3 axis leads
to expression of interleukin 6 (IL-6) and several chemokines. Moreover, the
activation of STAT3 signaling is dependent on PERK, a central component of the ER
stress response, which we show is phosphorylated by JAK1. Disruption of PERK
abrogates ER stress-induced activation of STAT3 and subsequent gene expression.
Additionally, ER-stressed astrocytes, via paracrine signaling, can stimulate
activation of microglia, leading to production of IL-6 and oncostatin M (OSM).
These IL-6 cytokines can then synergize with ER stress in astrocytes to drive
inflammation. Together, this work describes a new PERK/JAK1/STAT3 signaling
pathway that elicits a feed-forward inflammatory loop involving astrocytes and
microglia to drive neuroinflammation, which may be relevant in diseases such as
MS.
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