Sterile Inflammation in the Liver

Inflammation In the absence of pathogens occurs in all tissues in response to a wide range of stimuli that cause tissue stress and injury. Such sterile inflammation (SI) is a key process in drug-induced liver injury, nonalcoholic steatohepatitis, and alcoholic steatohepatitis and is a major determinant of fibrosis and carcinogenesis. In SI, endogenous damage-associated molecular patterns (DAMPS), which are usually hidden from the extracellular environment, are released on tissue injury and activate receptors on immune cells. More than 20 such DAMPS have been identified and activate cellular pattern recognition receptors, which were originally identified as sensors of pathogen-associated molecular patterns. Activation of pattern recognition receptors by DAMPS results in a wide range of immune responses, including production of proinflammatory cytokines and localization of immune cells to the site of injury. DAMPS result in the assembly of a cytosolic protein complex termed the inflammasome, which activates the serine protease caspase-1, resulting in activation and secretion of interleukin-1 beta and other cytokines. SI-driven liver diseases are responsible for the majority of liver pathology in industrially developed countries and lack specific therapy. Identification of DAMPS, their receptors, signaling pathways, and cytokines now provides a wide range of therapeutic targets for which many antagonists are already available.