Gulation of pPERK/peIF2/ATF4 and TLR2. The novel role of ATF4 in the regulation of TLR2 expression was confirmed using genetic and pharmacological approaches. Conclusions: xThe current study demonstrates that cocaine-mediated activation of microglia involves up-regulation of TLR2 through the ROS-ER stress-ATF4-TLR2 axis. Understanding the mechanism(s) involved in cocaine-mediated up-regulation of ROS-ER stress/TLR2 expression and microglial activation could have implications for the development of potential therapeutic targets aimed at CEP-37440MedChemExpress CEP-37440 resolving neuroinflammation in cocaine abusers. Keywords: Neuroinflammation, Cocaine, ER stress, Microglial activation, TLR2, ATFBackground Cocaine is one of most commonly used illicit drugs in the USA. More than 34 million Americans (16.2 ) aged 15 or older have used cocaine at least once in their lifetime [1]. A variety of disorders of the central nervous system (CNS) have been linked to chronic cocaine abuse including an increased risk of stroke and seizures, cognitive impairment, depression, and, in extreme cases, death [2]. Data from our group has shown that cocaine* Correspondence: [email protected] Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198, USAexposure induces the expression of chemokines and adhesion molecules by binding to its cognate receptor (-1R) expressed on a variety of cell types. This in turn may lead to an increased incidence and accelerated progression of HIV-associated neurocognitive disorders (HAND) [3]. Toll-like receptors (TLRs) are well known as a major family of pattern recognition receptors that play a critical role in innate host defense as well as in initiation of adaptive immune responses [4?]. Recent evidence reveals the expression of TLRs in the CNS where they exert many immune and non-immune functions [7].?2016 Liao et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/27107493 changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Liao et al. Journal of Neuroinflammation (2016) 13:Page 2 ofMore specifically, toll-like receptor-2 (TLR2) is widely expressed in the CNS, and a previous study demonstrated that morphine treatment resulted in up-regulation of TLR2 expression levels in primary microglial cells with a concomitant induction of pro-inflammatory cytokines [8]. However, there are no studies clearly delineating the role of TLR2 in cocaine-induced glial activation. The endoplasmic reticulum (ER) is well known to play a crucial role in multiple cellular functions such as protein folding, maintenance of Ca2+ balance, and cholesterol synthesis [9?1]. Both genetic and environmental insults can perturb the function of the ER and contribute to the development of ER stress. There are three primary stress sensors found in the ER: (1) inositol-requiring kinase 1 (IRE1), (2) protein kinase RNA-like endoplasmic reticulum kinase (PERK), and (3) activating transcription factor 6 (ATF6). When there is an imbalance betwee.
