Response of Human Liver Tissue to Innate Immune Stimuli.

Xia Wu,Camtu D Truong,Allison Knupp,Helen Horton,Keith R Jerome,Alexander L Greninger,David M Koelle,Ian N Crispe,Stephen J Polyak,Heidi L Kenerson,Marianne Tuefferd,Nicole Hollingshead,Jessica B Roberto,Antony Chen,Raymond S Yeung

doi:10.3389/fimmu.2022.811551

Abstract

Precision-cut human liver slice cultures (PCLS) have become an important alternative immunological platform in preclinical testing. To further evaluate the capacity of PCLS, we investigated the innate immune response to TLR3 agonist (poly-I:C) and TLR4 agonist (LPS) using normal and diseased liver tissue. Pathological liver tissue was obtained from patients with active chronic HCV infection, and patients with former chronic HCV infection cured by recent Direct-Acting Antiviral (DAA) drug therapy. We found that hepatic innate immunity in response to TLR3 and TLR4 agonists was not suppressed but enhanced in the HCV-infected tissue, compared with the healthy controls. Furthermore, despite recent HCV elimination, DAA-cured liver tissue manifested ongoing abnormalities in liver immunity: sustained abnormal immune gene expression in DAA-cured samples was identified in direct ex vivo measurements and in TLR3 and TLR4 stimulation assays. Genes that were up-regulated in chronic HCV-infected liver tissue were mostly characteristic of the non-parenchymal cell compartment. These results demonstrated the utility of PCLS in studying both liver pathology and innate immunity.

Highlights

We recently reported the development of Precision-cut human liver slice cultures (PCLS) as an immunological platform [1, 2]
The induction of these antiviral genes was greater with polycytidylic acid (poly-I):C compared with lipopolysaccharide endotoxin (LPS) treatment (Figures 1, S2)
We showed that immune abnormalities persist after the elimination of hepatitis C virus (HCV) by anti-viral therapy, and the persisting inflammatory and immune signatures featured genes characteristic of hepatic non-parenchymal cells

Summary

Introduction

The PCLS method has the advantage that hepatocytes and the major subsets of non-parenchymal cells (KC, LSEC and HSC) are cultured together in their normal anatomical relationships, enabling the analysis of liver cell function in the context of intercellular interaction. Steatotic liver slices retained fat droplets, and cholestatic liver slices displayed yellow-green pigment in hepatocytes. It remains unclear whether PCLS has the capacity to reveal alternations in innate immunity that may occur in pathological liver tissue as compared with healthy controls. As a proof of principle, we used PCLS to compare the dynamic responses of liver tissue collected from three groups of patients which included non-infected

Methods

Results

Conclusion