IL-1 Family Cytokine Pathways Underlying NAFLD: Towards New Treatment Strategies

• Published in: Trends in molecular medicine 2018-05, Vol.24 (5), p.458-471
• Main Authors: Mirea, Andreea-Manuela, Tack, Cees J., Chavakis, Triantafyllos, Joosten, Leo A.B., Toonen, Erik J.M.
• Format: Article
• Language: English
• Subjects: Animals; Caspase 1 - metabolism; Cytokines - metabolism; Humans; inflammasome; Inflammasomes - metabolism; inflammation; interleukin-1; Interleukin-1 - metabolism; Models, Biological; neutrophil serine proteases; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - metabolism; nonalcoholic fatty liver disease; obesity; Signal Transduction
• ISSN: 1471-4914; 1471-499X
• DOI: 10.1016/j.molmed.2018.03.005

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Pathways responsible for the activation of IL-1 family cytokines are key in the development of NAFLD but underlying mechanisms are not fully understood. Many studies have focused on the inflammasome–caspase-1 pathway and have shown that this pathway is an important inducer of inflammation in NAFLD. However, this pathway is not solely responsible for the activation of proinflammatory cytokines. Also, neutrophil serine proteases (NSPs) are capable of activating cytokines and recent studies reported that these proteases also contribute to NAFLD. These studies provided, for the first time, evidence that this inflammasome-independent pathway is involved in NAFLD. In our opinion, these new insights open up new approaches for therapeutic intervention. Cytokines are key in the development of NAFLD and NASH but mechanisms responsible for the activation of these cytokines are not fully understood. The NLRP3–inflammasome pathway is capable of activating cytokines and is a known inducer of inflammation in NAFLD and NASH. NSPs can also activate cytokines. Studies have now shown that NSPs are also involved in the development of NAFLD and NASH. The realization that NSPs are involved in NAFLD and NASH in an inflammasome-independent manner provides new insights into how inflammatory pathways contribute to these conditions. NSPs are inhibited by alpha-1 antitrypsin (AAT), and mice overexpressing AAT are protected against the development of NAFLD. Mice treated with AAT showed reduced hepatic lipid content in NAFLD mice models. The recent findings that NSPs contribute to NAFLD and NASH may open up perspectives for new therapeutics.