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Cited by 51Liver Disease Diagnosis and TreatmentInflammasome and immune disordersLiver physiology and pathology

Cell-specific Deletion of NLRP3 Inflammasome Identifies Myeloid Cells as Key Drivers of Liver Inflammation and Fibrosis in Murine Steatohepatitis

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Kaufmann, Benedikt, Kui, Lin, Reca, Agustina, Leszczynska, Aleksandra, Kim, Andrea D., Booshehri, Laela M., Wree, Alexander, Friess, Helmut +4 more·2022·Cellular and Molecular Gastroenterology and Hepatology
DOI 10.1016/j.jcmgh.2022.06.007PMC PMC9424559
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Abstract

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide. The NLRP3 inflammasome, a platform for caspase-1 activation and release of interleukin 1β, is increasingly recognized in the induction of inflammation and liver fibrosis during NAFLD. However, the cell-specific contribution of NLRP3 inflammasome activation in NAFLD remains unknown. METHODS: To investigate the role of NLRP3 inflammasome activation in hepatocytes, hepatic stellate cells (HSCs) and myeloid cells, a conditional Nlrp3 knock-out mouse was generated and bred to cell-specific Cre mice. Both acute and chronic liver injury models were used: lipopolysaccharide/adenosine-triphosphate to induce in vivo NLRP3 activation, choline-deficient, L-amino acid-defined high-fat diet, and Western-type diet to induce fibrotic nonalcoholic steatohepatitis (NASH). In vitro co-culture studies were performed to dissect the crosstalk between myeloid cells and HSCs. RESULTS: Myeloid-specific deletion of Nlrp3 blunted the systemic and hepatic increase in interleukin 1β induced by lipopolysaccharide/adenosine-triphosphate injection. In the choline-deficient, L-amino acid-defined high-fat diet model of fibrotic NASH, myeloid-specific Nlrp3 knock-out but not hepatocyte- or HSC-specific knock-out mice showed significant reduction in inflammation independent of steatosis development. Moreover, myeloid-specific Nlrp3 knock-out mice showed ameliorated liver fibrosis and decreased HSC activation. These results were validated in the Western-type diet model. In vitro co-cultured studies with human cell lines demonstrated that HSC can be activated by inflammasome stimulation in monocytes, and this effect was significantly reduced if NLRP3 was downregulated in monocytes. CONCLUSIONS: The study provides new insights in the cell-specific role of NLRP3 in liver inflammation and fibrosis. NLRP3 inflammasome activation in myeloid cells was identified as crucial for the progression of NAFLD to fibrotic NASH. These results may have implications for the development of cell-specific strategies for modulation of NLRP3 activation for treatment of fibrotic NASH.

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  • Inhibition of NLRP3 activation in myeloid cells demonstrated promising anti-fibrotic effects in murine models.

    “Similarly, while inhibition of inflammasome signaling, particularly NLRP3 activation in myeloid cells, demonstrated promising anti-fibrotic effects in murine models (142–144)”

    From Targeting macrophages in liver fibrosis (2026) · cites this paper as [142]

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Authors
Kaufmann, B., Kui, L., Reca, A., Leszczynska, A., Kim, A. D., Booshehri, L. M., Wree, A., Friess, H., Hartmann, D., Broderick, L., Hoffman, H. M., & Feldstein, A. E.
Affiliations
  • TUM Klinikum (DE)
  • University of California San Diego (US)
  • Charité – Universitätsmedizin Berlin (DE)
Corresponding author
Feldstein, Ariel E.
ORCID
Venue
Cellular and Molecular Gastroenterology and Hepatology
Publisher
Elsevier BV
Published
2022
Volume
14
Issue
4
Pages
751-767
ISSN
2352-345X (ISSN-L)
DOI
10.1016/j.jcmgh.2022.06.007
PMC
PMC9424559
OpenAlex
W4283780323
Cited by
51
References
6
Citations by year
2026: 9 · 2025: 12 · 2024: 13 · 2023: 15 · 2022: 2
FWCI
7.58
Type
journal article
Language
en
Update notices
erratum (2024-01-01)
Open access
Licence
Locations
  • Cellular and Molecular Gastroenterology and Hepatology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion, other-oa)
Funders
  • National Institutes of Health (R01 AA024206, R01 DK113592)
  • Deutsche Forschungsgemeinschaft (KA 5089/1-1)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
NLRP3 inflammasome, nonalcoholic steatohepatitis, liver fibrosis, liver inflammation, myeloid cells, hepatocytes, hepatic stellate cells, IL-1β, caspase-1, cell-specific gene deletion, choline-deficient high-fat diet, Western diet, monocytes
MeSH terms
NLR Family, Pyrin Domain-Containing 3 Protein, Adenosine, Amino Acids, Animals, Choline, Hepatitis, Humans, Inflammation, Lipopolysaccharides, Liver Cirrhosis, Polyphosphates, Mice, Knockout, Caspases, Myeloid Cells, Mice, Interleukin-1beta, Inflammasomes, Non-alcoholic Fatty Liver Disease

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