Leukotriene D4 Upregulates Oxidized Low-Density Lipoprotein Receptor 1 and CD36 to Enhance Oxidized LDL Uptake and Phagocytosis in Macrophages Through Cysteinyl Leukotriene Receptor 1.

Ernest Duah,Lakshminarayan Reddy Teegala,Sailaja Paruchuri,Charles K. Thodeti,Sabita Pokhrel,Ravindra Gudneppanavar

doi:10.3389/fphys.2021.756450

Ernest Duah, Lakshminarayan Reddy Teegala + Show 4 more

Open Access

https://doi.org/10.3389/fphys.2021.756450

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Abstract

Endothelial permeability, leukocyte attachment, and unregulated oxidized LDL (oxLDL) uptake by macrophages leading to the formation of foam cells are all vital in the initiation and progression of atherosclerosis. During inflammation, several inflammatory mediators regulate this process through the expression of distinct oxLDL binding cell surface receptors on macrophages. We have previously shown that Leukotriene D4 (LTD4) promotes endothelial dysfunction, increasing endothelial permeability and enhancing TNFα-mediated attachment of monocytes to endothelium, which hints at its possible role in atherosclerosis. Here we analyzed the effect of LTD4 on macrophage function. Macrophages mainly express CysLT1R and flux calcium in response to LTD4. Further, LTD4 potentiates phagocytosis in macrophages as revealed by the uptake of zymosan particles. Notably, LTD4 augmented macrophage phagocytosis and oxLDL uptake which is sensitive to MK-571 [Montelukast (MK)], a CysLT1R-specific antagonist. Mechanistically, LTD4 upregulated two receptors central to foam cell formation, oxidized low-density lipoprotein receptor-1 (OLR1/LOX-1), and CD36 in a time and dose-dependent manner. Finally, LTD4 enhanced the secretion of chemokines MCP-1 and MIP1β. Our results suggest that LTD4 contributes to atherosclerosis either through driving foam cell formation or recruitment of immune cells or both. CysLT1R antagonists are safely being used in the treatment of asthma, and the findings from the current study suggest that these can be re-purposed for the treatment of atherosclerosis.

Highlights

Macrophages are innate immune cells present ubiquitously in the body, and they are involved in the phagocytosis of foreign materials and pathogens (Han et al, 2016)
To understand the role of CysLTR signaling in regulating macrophage function, first we studied the expression of Cysteinyl Leukotriene 1 Receptor (CysLT1R) and Cysteinyl Leukotriene 2 Receptor (CysLT2R) in three different macrophage cell types- raw macrophages, THP-1-derived macrophages, and Bone marrow-derived macrophages (BMDM) by qPCR
Our results revealed that all macrophages mainly express CysLT1R compared to CysLT2R (Figures 1A–C)

Summary

INTRODUCTION

Macrophages are innate immune cells present ubiquitously in the body, and they are involved in the phagocytosis of foreign materials and pathogens (Han et al, 2016). Scavenger receptors function in scavenging self-antigens expressing damage associated molecular patterns (DAMPS) (Patten and Shetty, 2018), they facilitate phagocytosis of particles like oxLDL that are the products of oxidative stress (Woo et al, 2016). Since CysLTR signaling causes endothelial dysfunction, leading to enhanced vessel contraction and permeability facilitating monocyte attachment to endothelium, we explored their role in regulating macrophage function in the current study. While there have been many studies on macrophages, foam cell formation, and atherosclerosis, the involvement of cys-LTs or associated molecular mechanisms in macrophage function impacting atherosclerosis progression is elusive. In this study, we analyzed the role of cys-LTs in the uptake of oxidized LDL by macrophages, an initial step in the formation of foam cells, and the mechanism involved

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