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Critical Role of TLR4 Response in the Activation of Microglia Induced by Ethanol¹

Department of Cellular Pathology, Centro de Investigación Príncipe Felipe, Valencia, Spain

Microglial cells are the primary immune effector cells in the brain and play a pivotal role in the neuroinflammatory processes associated with a variety of neurological and pathological disorders. Alcohol consumption induces brain damage, although the neuropathological processes are poorly understood. We previously suggested that ethanol promotes inflammatory processes in the brain, up-regulating inflammatory mediators and signaling pathways associated with IL-1RI/TLR4 receptors. In the present study we investigate whether ethanol induces microglia activation by stimulating TLR4 response and whether this response causes neuronal death and contributes to ethanol-induced neuroinflammatory damage. We demonstrate that ethanol activates microglía and stimulates NF-B, MAPKs, and MyD88-independent (IFN regulatory factor-3, IFN-β) pathways to trigger the production of inflammatory mediators, causing neuronal death. The inflammatory response induced by ethanol is completely abrogated in microglia of TLR4-deficient mice (TLR4^–/–), thus supporting the role of these receptors in microglia activation and neuronal death. In accord with the in vitro findings, acute ethanol administration induces microglia activation (CD11b⁺ cells) in cerebral cortex of TLR4^+/+ mice, but not in TLR4^–/– mice. Taken together, our results not only provide the first evidence of the critical role of the TLR4 response in the ethanol-induced microglia activation, but also new insight into the basic mechanisms participating in ethanol-induced neuroinflammatory damage.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Spanish Ministry of Science and Innovation (SAF 2006-02178, SAF 2009-07503), The Ministry of Health, Carlos III Institute (RTA Network, G03/005), PNSD (G46923421), General Direction of Drug Dependence (GV), and the Fundación de Investigación Médica Mutua Madrileña.

² S.F.-L. and M.P. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Consuelo Guerri, Department of Cellular Pathology, Centro de Investigación Príncipe Felipe, Avenida Autopista del Saler 16, 46012 Valencia, Spain. E-mail address: guerri{at}cipf.es

⁴ Abbreviations used in this paper: TRIF, Toll/IL-1RI containing adaptor-inducing IFN-β; COX-2, cyclooxygenase-2; iNOS, inducible NO synthase; IRAK, IL-1R-associated kinase; IRF, IFN regulatory factor; LTA, lipoteichoic acid; PMBS, polymyxin B sulfate; TRAM, Toll receptor-associated molecule.