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World J Gastroenterol. Nov 28, 2014; 20(44): 16443-16451
Published online Nov 28, 2014. doi: 10.3748/wjg.v20.i44.16443
Toll-like receptor-mediated signaling cascade as a regulator of the inflammation network during alcoholic liver disease
Sara Ceccarelli, Valerio Nobili, Anna Alisi
Sara Ceccarelli, Valerio Nobili, Anna Alisi, Hepato-Metabolic Disease Unit and Liver Research Unit, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
Author contributions: Ceccarelli S, Nobili V and Alisi A contributed equally to the conception, drafting and approval of this manuscript.
Supported by Associazione Italiana per la Ricerca sul Cancro (AIRC), Grant No. MFAG 12936 (to Anna Alisi)
Correspondence to: Anna Alisi, PhD, Hepato-Metabolic Disease Unit and Liver Research Unit, Bambino Gesù Children’s Hospital, IRCCS, S. Onofrio Square 4, 00165 Rome, Italy. anna.alisi@opbg.net
Telephone: +39-6-68592186 Fax: +39-6-68592904
Received: May 28, 2014
Revised: August 8, 2014
Accepted: September 29, 2014
Published online: November 28, 2014
Processing time: 187 Days and 13.8 Hours
Abstract

Chronic abuse of alcohol leads to various histological abnormalities in the liver. These are conditions collectively known as alcoholic liver disease (ALD). Currently, ALD is considered to be one of the major causes of death worldwide. An impaired intestinal barrier with related endotoxemia is among the various pathogenetic factors. This is mainly characterized by circulating levels of lipopolysaccharide (LPS), considered critical for the onset of intra-hepatic inflammation. This in turn promotes hepatocellular damage and fibrosis in ALD. Elevated levels of LPS exert their effects by binding to Toll-like receptors (TLRs) which are expressed by all liver-resident cells. The activation of TLR signaling triggers an overproduction and release of some cytokines, which promote an autocatalytic cascade of other pro-inflammatory signals. In this review, we provide an overview of the mechanisms that sustain LPS-mediated activation of TLR signaling, reporting current experimental and clinical evidence of its role during inflammation in ALD.

Keywords: Alcoholic liver disease; Toll-like receptors; Inflammation; Cirrhosis; Nuclear factor-κB; Cytokines

Core tip: Alcoholic liver disease (ALD) pathogenesis is quite complex and requires the activation/inhibition of several molecular pathways. The inflammatory storm caused by alcohol abuse on the gut-liver axis and consequent activation of Toll-like receptor (TLR) signaling is topical for researchers and physicians, both for understanding ALD pathophysiology and for translating novel clues into clinical practice. Here, we focus on the current evidence of TLR involvement in inflammation during ALD in experimental models and humans, offering readers with no first-hand knowledge of this topic a valuable tool to start novel studies.