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Toll‐Like Receptor 9 Signals through both the Stress‐tolerance and Inflammatory Cascades after Pharmacological Stimulation in Isolated Rat Arteries
Author(s) -
McCarthy Cameron,
Wenceslau Camilla,
Goulopoulou Styliani,
Webb R Clinton
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.783.2
Subject(s) - tlr9 , signal transduction , unfolded protein response , endoplasmic reticulum , microbiology and biotechnology , endocrinology , receptor , medicine , stimulation , tlr4 , biology , chemistry , biochemistry , gene expression , gene , dna methylation
Traditionally, activation of Toll‐like receptor (TLR)9 involves an intracytoplasmic signaling cascade that proceeds through MyD88. However, recently it was observed that TLR9 participates in an alternative non‐canonical‐stress tolerance signaling cascade in non‐immune cells. In this novel signaling pathway, TLR9 stimulation reduces SERCA2 activity, modulating calcium homeostasis between the endoplasmic reticulum and mitochondria, which leads to a decrease in ATP levels and the activation of 5' AMP‐activated protein kinase (AMPK)α. We hypothesized that this non‐canonical‐stress tolerance TLR9 signaling cascade also participates in vascular tissues. Isolated mesenteric resistance arteries from Wistar rats were divided into four parts for Western blot analysis. One part was flash frozen to determine basal expression, the other three parts were incubated in synthetic TLR9 agonist ODN2395 (2 μM) for either 15, 30 min, or 30 min with TLR9 antagonist, ODN2088. ODN2395 changed protein expression of both the canonical‐inflammatory TLR9 signaling (increased MyD88 and TRAF6) (p<0.05 vs. basal), as well as the non‐canonical‐stress tolerance TLR9 signaling (increased SERCA2 and decreased phospho‐AMPK) (p<0.05 vs. basal). We conclude that vascular tissues present both the canonical‐inflammatory TLR9 signaling, as well as the non‐canonical‐stress tolerance TLR9 signaling. Therefore, this novel signaling cascade could be a pharmacological target in diseases where TLR9 is involved (e.g. hypertension).