1. The heavy subunit of ferritin stimulates NLRP3 inflammasomes in hepatic stellate cells through ICAM-1 to drive hepatic inflammation.
- Author
-
Fernandez-Rojo, Manuel A., Pearen, Michael A., Burgess, Anita G., Ikonomopoulou, Maria P., Hoang-Le, Diem, Genz, Berit, Saggiomo, Silvia L., Nawaratna, Sujeevi S. K., Poli, Maura, Reissmann, Regina, Gobert, Geoffrey N., Deutsch, Urban, Engelhardt, Britta, Brooks, Andrew J., Jones, Alun, Arosio, Paolo, and Ramm, Grant A.
- Subjects
FERRITIN ,LIVER cells ,NLRP3 protein ,CELL adhesion molecules ,INFLAMMASOMES ,INTERLEUKIN-1 receptors ,CHRONIC active hepatitis ,COATED vesicles - Abstract
Serum ferritin concentrations increase during hepatic inflammation and correlate with the severity of chronic liver disease. Here, we report a molecular mechanism whereby the heavy subunit of ferritin (FTH) contributes to hepatic inflammation. We found that FTH induced activation of the NLRP3 inflammasome and secretion of the proinflammatory cytokine interleukin-1β (IL-1β) in primary rat hepatic stellate cells (HSCs) through intercellular adhesion molecule–1 (ICAM-1). FTH–ICAM-1 stimulated the expression of Il1b, NLRP3 inflammasome activation, and the processing and secretion of IL-1β in a manner that depended on plasma membrane remodeling, clathrin-mediated endocytosis, and lysosomal destabilization. FTH–ICAM-1 signaling at early endosomes stimulated Il1b expression, implying that this endosomal signaling primed inflammasome activation in HSCs. In contrast, lysosomal destabilization was required for FTH-induced IL-1β secretion, suggesting that lysosomal damage activated inflammasomes. FTH induced IL-1β production in liver slices from wild-type mice but not in those from Icam1
−/− or Nlrp3−/− mice. Thus, FTH signals through its receptor ICAM-1 on HSCs to activate the NLRP3 inflammasome. We speculate that this pathway contributes to hepatic inflammation, a key process that stimulates hepatic fibrogenesis associated with chronic liver disease. Editor's summary: The multisubunit protein ferritin stores iron inside cells but is released into the circulation during acute hepatitis and in chronic liver disease. Hepatic stellate cells (HSCs) are myofibroblasts that, when activated, drive the inflammation and fibrosis that lead to the progressive loss of liver function. Fernandez-Rojo et al. found that the ferritin heavy subunit (FTH) stimulated inflammasome activation in rat and human HSCs and in liver slices from mice. FTH bound to the cell adhesion molecule ICAM-1 on HSCs and was endocytosed, leading to the priming and activation of NLRP3-containing inflammasomes and subsequent secretion of the proinflammatory cytokine IL-1β. The findings suggest that FTH is a damage-induced molecular pattern that contributes to the hepatic inflammation that drives liver dysfunction. —Annalisa M. VanHook [ABSTRACT FROM AUTHOR]- Published
- 2024
- Full Text
- View/download PDF