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

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.
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Submitted on : Monday, May 6, 2019 - 11:43:43 AM
Last modification on : Tuesday, August 13, 2019 - 3:04:04 PM

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Sacha Robert, Thomas Gicquel, Aude Bodin, Alain Fautrel, Emiliano Barreto, et al.. Influence of inflammasome pathway activation in macrophages on the matrix metalloproteinase expression of human hepatic stellate cells. International Immunopharmacology, Elsevier, 2019, 72, pp.12-20. ⟨10.1016/j.intimp.2019.03.060⟩. ⟨hal-02120881⟩

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