FIGURE 2. Mechanisms of Sensing of the Hepatocyte Damage and Amplification of Inflammation by Intestinal Epithelial Cells.

In cirrhosis, chronic ischemia and reperfusion of hepatocytes activates sinusoidal Kuppfer cells, leading to production of pro-inflammatory mediators such as TNF-α, IL-1α, and IL-6. Damaged hepatocytes alert immune system by releasing damage-associated molecular pattern molecules (DAMPs) such as High mobility group box-1 (HMGB1), histones, and uric acids into the systemic circulation. Those pro-inflammatory signals are sensed by intestinal immune system, in which reserve the largest population of immune cells. DAMPs may activate the toll-like receptor (TLR) family in the intestinal epithelial cells (e.g., Paneth cells) and innate immune cells (Dendrite cells). Binding of DMAPs to TLR receptor on the Dendrite cells triggers the production of pro-inflammatory mediators such as TNF-α and IL-6 and IL-1β. Also the binding of DAMPs to TLR receptors in Paneth cells triggers the release of stored IL-17A from Paneth cells. Abbreviations DAMP, Damage Associated Molecular Pattern, IL-1, interleukin-1, IL-17, interleukin-17, MYD-88, Myeloid differentiation primary response gene 88, TNF-α, Tumor Necrosis Factor-α, TLR, Toll Like Receptor, TRAM, TRIF-related adaptor molecule, TRIF, TIR-domain-containing adapter-inducing interferon-β