1. The heavy subunit of ferritin stimulates NLRP3 inflammasomes in hepatic stellate cells through ICAM-1 to drive hepatic inflammation.
- Author
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Fernandez-Rojo MA, Pearen MA, Burgess AG, Ikonomopoulou MP, Hoang-Le D, Genz B, Saggiomo SL, Nawaratna SSK, Poli M, Reissmann R, Gobert GN, Deutsch U, Engelhardt B, Brooks AJ, Jones A, Arosio P, and Ramm GA
- Subjects
- Rats, Mice, Animals, NLR Family, Pyrin Domain-Containing 3 Protein genetics, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Intercellular Adhesion Molecule-1 genetics, Intercellular Adhesion Molecule-1 metabolism, Hepatic Stellate Cells metabolism, Ferritins genetics, Ferritins metabolism, Interleukin-1beta metabolism, Inflammation genetics, Inflammation metabolism, Inflammasomes genetics, Inflammasomes metabolism, Liver Diseases
- 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.- Published
- 2024
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