NOD-like receptor protein 3 activation causes spontaneous inflammation and fibrosis that mimics human NASH.

Abstract

BACKGROUND AND AIMS:

The NOD-like receptor protein 3 (NLRP3) inflammasome is a central contributor to human acute and chronic liver disease, yet the molecular and cellular mechanisms by which its activation precipitates injury remain incompletely understood. Here, we present single cell transcriptomic profiling of livers from a global transgenic tamoxifen-inducible constitutively activated Nlrp3A350V mutant mouse, and we investigate the changes in parenchymal and nonparenchymal liver cell gene expression that accompany inflammation and fibrosis.

APPROACH AND RESULTS:

Our results demonstrate that NLRP3 activation causes chronic extramedullary myelopoiesis marked by myeloid progenitors that differentiate into proinflammatory neutrophils, monocytes, and monocyte-derived macrophages. We observed prominent neutrophil infiltrates with increased Ly6gHI and Ly6gINT cells exhibiting transcriptomic signatures of granulopoiesis typically found in the bone marrow. This was accompanied by a marked increase in Ly6cHI monocytes differentiating into monocyte-derived macrophages that express transcriptional programs similar to macrophages of NASH models. NLRP3 activation also down-regulated metabolic pathways in hepatocytes and shifted hepatic stellate cells toward an activated profibrotic state based on expression of collagen and extracellular matrix regulatory genes.

CONCLUSIONS:

These results define the single cell transcriptomes underlying hepatic inflammation and fibrosis precipitated by NLRP3 activation. Clinically, our data support the notion that NLRP3-induced mechanisms should be explored as therapeutic target in NASH-like inflammation.

• Authors: David M Calcagno, Angela Chu, Susanne Gaul, Nika Taghdiri, Avinash Toomu, Aleksandra Leszczynska, Benedikt Kaufmann, Bettina Papouchado, Alexander Wree, Lukas Geisler, Hal M Hoffman, Ariel E Feldstein, Kevin R King
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 76 Issue 3 Pg. 727-741 (09 2022) ISSN: 1527-3350 [Electronic] United States
• PMID: 34997987 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2022 American Association for the Study of Liver Diseases.

Chemical References

• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLR Proteins

Topics

• Animals
• Fibrosis
• Humans
• Inflammasomes (metabolism)
• Inflammation
• Mice
• NLR Family, Pyrin Domain-Containing 3 Protein (physiology)
• NLR Proteins
• Non-alcoholic Fatty Liver Disease