7/4/24, 16:19 The heavy subunit of ferritin stimulates NLRP3 inflammasomes in hepatic stellate cells through ICAM-1 to drive

te cells through ICAM-1 to drive hepatic inflammation | Science Signaling

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HOME  SCIENCE SIGNALING  VOL. 17, NO. 830  THE HEAVY SUBUNIT OF FERRITIN STIMULATES NLRP3 INFLAMMASOMES IN HEPATIC STELLATE CELLS THROUGH ICAM-1 TO DRIVE…

 RESEARCH ARTICLE INFLAMMATION

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The heavy subunit of ferritin stimulates NLRP3 inflammasomes in
hepatic stellate cells through ICAM-1 to drive hepatic inflammation
MANUEL A. FERNANDEZ-ROJO
 , MICHAEL A. PEAREN , [...], AND GRANT A. RAMM  +14 authors Authors Info & Affiliations

SCIENCE SIGNALING 2 Apr 2024 Vol 17, Issue 830 DOI: 10.1126/scisignal.ade4335

505
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Editor’s summary

The multisubunit protein ferritin stores iron inside cells but is released into the circulation during acute hep-
atitis 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 proinflam-
matory 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

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 inter-
cellular 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 remod-
eling, clathrin-mediated endocytosis, and lysosomal destabilization. FTH–ICAM-1 signaling at early endo-
somes 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 ac-
tivate the NLRP3 inflammasome. We speculate that this pathway contributes to hepatic inflammation, a key
process that stimulates hepatic fibrogenesis associated with chronic liver disease.

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7/4/24, 16:19 The heavy subunit of ferritin stimulates NLRP3 inflammasomes in hepatic stellate cells through ICAM-1 to drive hepatic inflammation | Science Signaling

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REFERENCES AND NOTES

1 T. Ganz, E. Nemeth, Hepcidin and disorders of iron metabolism. Annu. Rev. Med. 62, 347–360 (2011).

CROSSREF • PUBMED • ISI • GOOGLE SCHOLAR

2 M. W. Hentze, M. U. Muckenthaler, B. Galy, C. Camaschella, Two to tango: Regulation of Mammalian iron metabolism. Cell 142, 24–38 (2010).

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3 M. J. Wood, D. H. Crawford, L. F. Wockner, L. W. Powell, G. A. Ramm, Serum ferritin concentration predicts hepatic fibrosis better than hepatic
iron concentration in human HFE-Haemochromatosis. Liver Int. 37, 1382–1388 (2017).

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4 K. Jurczyk, M. Wawrzynowicz-Syczewska, A. Boron-Kaczmarska, Z. Sych, Serum iron parameters in patients with alcoholic and chronic cirrho-
sis and hepatitis. Med. Sci. Monit. 7, 962–965 (2001).

PUBMED • GOOGLE SCHOLAR

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7/4/24, 16:19 The heavy subunit of ferritin stimulates NLRP3 inflammasomes in hepatic stellate cells through ICAM-1 to drive hepatic inflammation | Science Signaling

The heavy subunit of ferritin stimulates NLRP3 inflammasomes in hepatic stellate cells through ICAM-1 to drive hepatic inflammation
BY MANUEL A. FERNANDEZ-ROJO, MICHAEL A. PEAREN, ET AL.

Lipid drops in on Alzheimer’s disease

BY AMY E. BAEK

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