High-density lipoprotein suppresses tumor necrosis factor alpha production by mycobacteria-infected human macrophages

Manabu Inoue,Yuriko Ozeki,Yukihiro Kaneko,Mamiko Niki,Makoto Matsumoto,Mayuko Osada-Oka,Sammy M Njenga,Sohkichi Matsumoto,Tetsuya Oda,Evans Asena Chadeka,Takehiro Yamaguchi,Shinjiro Hamano,Shinjiro Hamano,Kenji Ono,Yoshio Ichinose,Satoshi Kaneko,Satoshi Kaneko,Sachiyo Nagi,Faith Mwende

doi:10.1038/s41598-018-24233-1

Abstract

Immune responses to parasitic pathogens are affected by the host physiological condition. High-density lipoprotein (HDL) and low-density lipoprotein (LDL) are transporters of lipids between the liver and peripheral tissues, and modulate pro-inflammatory immune responses. Pathogenic mycobacteria are parasitic intracellular bacteria that can survive within macrophages for a long period. Macrophage function is thus key for host defense against mycobacteria. These basic facts suggest possible effects of HDL and LDL on mycobacterial diseases, which have not been elucidated so far. In this study, we found that HDL and not LDL enhanced mycobacterial infections in human macrophages. Nevertheless, we observed that HDL remarkably suppressed production of tumor necrosis factor alpha (TNF-α) upon mycobacterial infections. TNF-α is a critical host-protective cytokine against mycobacterial diseases. We proved that toll-like receptor (TLR)-2 is responsible for TNF-α production by human macrophages infected with mycobacteria. Subsequent analysis showed that HDL downregulates TLR2 expression and suppresses its intracellular signaling pathways. This report demonstrates for the first time the substantial action of HDL in mycobacterial infections to human macrophages.

Highlights

Immune responses to parasitic pathogens are affected by the host physiological condition
Mycobacteria-infected human macrophages produce a large amount of TNF-α, which is suppressed by High-density lipoprotein (HDL)
We confirmed no significant differences in the viability rates of cells by addition of 5 to 50 μg/ml HDL or low-density lipoprotein (LDL), based on the results of the trypan blue-exclusion assays or assessment of cytoplasmic lactate dehydrogenase (LDH) enzyme activity in the culture medium

Summary

Introduction

Immune responses to parasitic pathogens are affected by the host physiological condition. High-density lipoprotein (HDL) and low-density lipoprotein (LDL) are transporters of lipids between the liver and peripheral tissues, and modulate pro-inflammatory immune responses. Macrophage function is key for host defense against mycobacteria These basic facts suggest possible effects of HDL and LDL on mycobacterial diseases, which have not been elucidated so far. A high level of LDL-C is a risk factor for cardiovascular diseases[1,2] because it initiates atherosclerosis, leading to peripheral inflammations including the production of inflammatory cytokines and accumulation of macrophages and activated T cells. A key pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-α), activates macrophages and is essential for granuloma formation. The immunomodulatory effects of cholesterol transporters, LDL and HDL, on mycobacterial diseases remain to be elucidated. We assessed the action of LDL and HDL on mycobacteria-infected human macrophages

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Results

Conclusion