Influence of inflammasome pathway activation in macrophages on the matrix metalloproteinase expression of human hepatic stellate cells

Sacha Robert, Thomas Gicquel, Aude Bodin, Alain Fautrel, Emiliano Barreto, Tatiana Victoni, Vincent Lagente, Elisabeth Boichot

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Inflammasomes are protein complexes that produce IL-1β in response to damage or pathogens. As such, inflammasomes are involved in several types of hepatic fibrosis. However, the mechanisms by which these complexes drive the liver's fibrogenic status remain unclear. We co-cultured differentiated macrophages (the THP-1 cell line or human monocyte-derived macrophages (MDMs)) with human hepatic fibroblasts (either the LX-2 cell line or primary human hepatic stellate cells (HSCs)). The inflammasome pathway was activated with lipopolysaccharide (LPS) and monosodium urate (MSU) crystals, and the HSCs' responses were analyzed. Our results show that co-culture of HSCs with THP-1 cells upregulated transcription of the genes coding for metalloproteinase (MMP)-3 and MMP-9. After inflammasome pathway activation, the HSCs' phenotype was the same in the presence of THP-1 cells or MDMs (i.e. upregulation of MMP-3, MMP-9, and the pro-inflammatory cytokine IL-1β). We found that two cytokines were involved in these changes: IL-1β regulated MMP-3 and IL-1β mRNA expression, whereas TNF-α regulated MMP-9 mRNA expression. Experiments with primary cells revealed that a general inflammatory environment is responsible for the downregulation of pro-fibrotic markers. Our present results suggest that inflammasome pathway activation in macrophages leads to a pro-inflammatory environment for HSCs leading to MMP/TIMP imbalance and enhanced fibrolytic properties.

Original languageEnglish (US)
Pages (from-to)12-20
Number of pages9
JournalInternational Immunopharmacology
Volume72
DOIs
StatePublished - Jul 2019
Externally publishedYes

Bibliographical note

Funding Information:
We thank Dr. S.L. Friedman (Mount Sinai School of Medicine, New York, NY, USA) for his generous gift of LX-2 cells. We thank CNPq for the Special Visiting Researcher Fellowship (PVE) awarded to Professor Vincent Lagente at the Federal University of Rio de Janeiro, as part of the Brazilian Scientific Mobility Program (Ciências sem Fronteiras; grant number: 303452/2014-5), and the postdoctoral grant awarded to Professor Emiliano Barreto at the University of Rennes 1 as part of the same program (grant number: 203537/2014-9). Lastly, we thank the Centre de Ressources Biologiques Santé (Rennes, France; reference BB-0033-00056) for managing the patient samples.

Publisher Copyright:
© 2019 Elsevier B.V.

Keywords

  • Cytokine
  • Hepatic stellate cell
  • Inflammasome
  • Macrophage
  • Metalloproteinase

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