Journal
DIGESTIVE DISEASES AND SCIENCES
Volume 61, Issue 5, Pages 1294-1303Publisher
SPRINGER
DOI: 10.1007/s10620-016-4049-x
Keywords
Liver disease; Cell death; Innate immunity; Inflammation; Therapy; NASH
Categories
Funding
- NIH [R01 DK082451, U01 AA022489]
- Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT) from Government of Chile [1150327, PD3140396]
- Comision Nacional de Investigacion Cientifica y Tecnologica from Government of Chile [PFB 12/2007]
- Millennium Institute on Immunology and Immunotherapy, Santiago Chile
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Inflammation and hepatocyte injury and death are the hallmarks of nonalcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver disease (NAFLD), which is a currently burgeoning public health problem. Innate immune activation is a key factor in triggering and amplifying hepatic inflammation in NAFLD/NASH. Thus, identification of the underlying mechanisms by which immune cells in the liver recognize cell damage signals or the presence of pathogens or pathogen-derived factors that activate them is relevant from a therapeutic perspective. In this review, we present new insights into the factors promoting the inflammatory response in NASH including sterile cell death processes resulting from lipotoxicity in hepatocytes as well as into the altered gut-liver axis function, which involves translocation of bacterial products into portal circulation as a result of gut leakiness. We further delineate the key immune cell types involved and how they recognize both damage-associated molecular patterns or pathogen-associated molecular patterns through binding of surface-expressed pattern recognition receptors, which initiate signaling cascades leading to injury amplification. The relevance of modulating these inflammatory signaling pathways as potential novel therapeutic strategies for the treatment of NASH is summarized.
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