The CD14+/CD16+subset of human blood monocytes, which expresses low levels of the lipopolysaccharide receptor CD14 and high levels of the Fc receptor CD16 and exhibits features of mature tissue mac...

https://www.physiology.org/doi/pdf/10.1152/ajpheart.1999.276.4.H1144

Distinct scavenger receptor expression and function in the human CD14+/CD16+monocyte subset

—We examined the effect of acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibitors on intracellular cholesterol stores in primary human monocyte–derived macrophages (HMMs) during foam cell formation. HMMs were exposed to acetylated low density lipoprotein (acLDL, 500 μg protein per mL) with or without 58-035 (1 to 10 μg/mL) or CI-976 (2 μg/mL) for 2 to 48 hours. Total cholesterol (TC) and esterified cholesterol (EC) mass was significantly lower while unesterified cholesterol (UC) increased slightly in cells incubated with acLDL plus ACAT inhibitors. Sterol mass was also measured in cells coincubated with acLDL (500 μg protein per mL) with or without 58-035 (2 μg/mL), high density lipoprotein (HDL, 400 μg protein per mL), or HDL+58-035 for 48 hours. TC and EC were 23% and 55% lower, respectively ( P <0.0004), while UC was 11% higher ( P <0.04) in cells incubated with acLDL plus 58-035. In contrast, coincubation with HDL alone did not significantly affect TC, EC, or UC mass compared with acLDL alone. The effect of 58-035 could not be explained by cytotoxicity, because adenine release, secreted lactate dehydrogenase, glucose utilization, and cell protein were similar in cells exposed to acLDL regardless of the presence of 58-035. We investigated several potential mechanisms for the decreased TC mass, including increased UC efflux and decreased acLDL binding and uptake. Efflux was measured in cells exposed to [1,2-3H]cholesteryl oleate–labeled acLDL, unlabeled control acLDL, and native untreated acLDL (500 μg protein per mL) with or without 58-035 (5 μg/mL) for 24 or 48 hours. UC efflux increased in a time-dependent manner from cells exposed to acLDL plus 58-035 compared with cells exposed to acLDL alone ( P <0.04). High-affinity binding was measured in cells exposed to 125I-acLDL (5 μg protein per mL) with or without excess unlabeled acLDL (100 or 500 μg protein per mL) for 4 hours at 4°C. Specific acLDL binding, uptake, and total degradation were significantly lower when 58-035 was present during cholesterol enrichment compared with cells exposed to acLDL alone ( P <0.001). Unlike the effects of ACAT inhibitors on foam cell formation in rodent macrophages, these compounds lowered TC accumulation in HMMs during foam cell formation by limiting the uptake of acLDL and enhancing UC efflux. They may offer promise as drug therapies for atherosclerosis.

Novel Effects of the Acyl-Coenzyme A:Cholesterol Acyltransferase Inhibitor 58-035 on Foam Cell Development in Primary Human Monocyte–Derived Macrophages

Objective

Reactive arthritis (ReA) is postulated to be caused by a defective host defense against gram-negative bacteria. HLA–B27 could play a role in this process, but does not account for the many HLA–B27 negative patients. The objective of this study was to test the expression of 3 macrophage scavenger receptors (SRs) that are responsible for innate immunity against gram-negative bacteria: SR class A type I (SR-AI), SR-AII, and the macrophage receptor with collagenous structure (MARCO). We postulate that defects in such receptors might also contribute to the host risk factors that increase the predisposition to ReA and perhaps other subtypes of spondylarthropathy (SpA).



Methods

Peripheral blood, synovial fluid, and synovial tissue samples were obtained from patients with recent Salmonella infection, ReA, other SpA, and rheumatoid arthritis (RA). The expression of SRs receptors was assessed by semiquantitative reverse transcriptase–polymerase chain reaction.



Results

Evaluation of the peripheral blood mononuclear cells (PBMC) from 4 patients who were recently infected with Salmonella, showed that PBMC from 2 patients who developed ReA expressed positive levels of MARCO, while PBMC from 2 patients who recovered from infection without sequelae did not. The synovial fluid mononuclear cells (SFMC) from some ReA patients expressed MARCO, but the levels were only moderate. The level of MARCO in the SFMC from the SpA patient group was low. In marked contrast, MARCO expression was high in almost all samples of RA SFMC. These findings also extended to synovial tissues.



Conclusion

Expression of the host defense gene MARCO was susceptible to modulation, not only during infections, but also in the inflammatory arthritis conditions RA and SpA. MARCO is a variable to be considered as a candidate factor that might contribute to ReA.

Expression of host defense scavenger receptors in spondylarthropathy.

Enzymatically modified low-density lipoprotein upregulates CD36 in low-differentiated monocytic cells in a peroxisome proliferator-activated receptor-γ-dependent way

The binding in vitro of modified LDL to the intermediate filament protein vimentin.

We recently reported that the human monocytic Mono Mac 6sr cell line constitutively takes up and degrades acetylated (acLDL) and oxidized LDL through receptor-specific pathways. The present studies were undertaken to further characterize the acLDL binding site on a functional and molecular basis. The degradation of acLDL increased during differentiation of Mono Mac 6sr cells with lipopolysaccharide (10 ng/mL, 72 hours) and low concentrations of phorbol 12-myristate 13-acetate (PMA; 0.1 to 1.0 ng/mL, 72 hours). Higher doses of PMA (5 or 10 ng/mL), however, decreased acLDL degradation. Scatchard plots of acLDL binding in untreated and LPS-differentiated Mono Mac 6sr cells were nonlinear and suggested the presence of more than one binding site. Although the ligand specificity of the acLDL receptor in Mono Mac 6sr cells resembles that of the macrophage type I and type II scavenger receptors, we did not detect mRNA of either receptor type in untreated or differentiated Mono Mac 6sr cells by means of Northern blotting and reverse transcription polymerase chain reaction. Furthermore, ligand blotting with 125I-acLDL failed to detect the 220-kD types I and II scavenger receptor protein. Thus, Mono Mac 6sr cells express an acLDL receptor that is distinct from the type I and type II scavenger receptor found in human monocyte–derived macrophages but that, like the latter, is induced during monocytic differentiation.

Acetylated LDL Endocytosis by the Human Monocytic Mono Mac 6sr Cells Is Not Mediated by the Macrophage Type I and II Scavenger Receptors

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Acetylated LDL Endocytosis by the Human Monocytic Mono Mac 6sr Cells Is Not Mediated by the Macrophage Type I and II Scavenger Receptors