Transcriptome and proteome profiling reveal complementary scavenger and immune features of rat liver sinusoidal endothelial cells and liver macrophages

• Published in: BMC cell biology Vol. 21; no. 1; pp. 1 - 85
• Main Authors: Bhandari, Sabin, Li, Ruomei, Simón-Santamaría, Jaione, McCourt, Peter, Johansen, Steinar Daae, Smedsrad, Bård, Martinez-Zubiaurre, Inigo, Sarensen, Karen Kristine
• Format: Journal Article
• Language: English
• Published: London BioMed Central Ltd 27.11.2020; BioMed Central; BMC
• Subjects: Antigen presentation; Antigen processing; Basale medisinske, odontologiske og veterinærmedisinske fag: 710; Basic medical, dental and veterinary science disciplines: 710; CD11b antigen; Chemokines; Endocytosis; Endothelial cells; Endothelium; Experiments; Gene expression; Genes; Genetic aspects; Health aspects; Hepatocytes; Immune clearance; Immune response; Immunosuppressive agents; Kupffer cells; Lectins; Liver; Lymphocytes; Macrophages; Mannose; Medical disciplines: 700; Medisinske Fag: 700; Monoclonal antibodies; Nanoparticles; Phenotypes; Physiological aspects; Principal components analysis; Protein expression; Proteins; Proteomes; Proteomics; Scanning electron microscopy; Scavenger receptors; Sinusoidal endothelial cells; Sprague Dawley rat; Toxicity; Transcriptomics; VDP; Xenobiotics; Norway
• ISSN: 2661-8850; 2661-8850; 1471-2121
• DOI: 10.1186/s12860-020-00331-9

Liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs; liver resident macrophages) form the body's most effective scavenger cell system for the removal of harmful blood-borne substances, ranging from modified self-proteins to pathogens and xenobiotics. Controversies in the literature regarding the LSEC phenotype pose a challenge when determining distinct functionalities of KCs and LSECs. This may be due to overlapping functions of the two cells, insufficient purification and/or identification of the cells, rapid dedifferentiation of LSECs in vitro, or species differences. We therefore characterized and quantitatively compared expressed gene products of freshly isolated, highly pure LSECs (fenestrated SE-1/Fc[gamma]RIIb2.sup.+) and KCs (CD11b/c.sup.+) from Sprague Dawley, Crl:CD (SD), male rats using high throughput mRNA-sequencing and label-free proteomics. We observed a robust correlation between the proteomes and transcriptomes of the two cell types. Integrative analysis of the global molecular profile demonstrated the immunological aspects of LSECs. The constitutive expression of several immune genes and corresponding proteins of LSECs bore some resemblance with the expression in macrophages. LSECs and KCs both expressed high levels of scavenger receptors (SR) and C-type lectins. Equivalent expression of SR-A1 (Msr1), mannose receptor (Mrc1), SR-B1 (Scarb1), and SR-B3 (Scarb2) suggested functional similarity between the two cell types, while functional distinction between the cells was evidenced by LSEC-specific expression of the SRs stabilin-1 (Stab1) and stabilin-2 (Stab2), and the C-type lectins LSECtin (Clec4g) and DC-SIGNR (Clec4m). Many immune regulatory factors were differentially expressed in LSECs and KCs, with one cell predominantly expressing a specific cytokine/chemokine and the other cell the cognate receptor, illustrating the complex cytokine milieu of the sinusoids. Both cells expressed genes and proteins involved in antigen processing and presentation, and lymphocyte co-stimulation. Our findings support complementary and partly overlapping scavenging and immune functions of LSECs and KCs. This highlights the importance of including LSECs in studies of liver immunity, and liver clearance and toxicity of large molecule drugs and nano-formulations.