Endoplasmic Reticulum Stress in Macrophages: The Vicious Circle of Lipid Accumulation and Pro-Inflammatory Response

Abstract

The endoplasmic reticulum (ER) stress is an important event in the pathogenesis of different human disorders, including atherosclerosis. ER stress leads to disturbance of cellular homeostasis, apoptosis, and in the case of macrophages, to foam cell formation and pro-inflammatory cytokines production. In atherosclerosis, several cell types can be affected by ER stress, including endothelial cells, vascular smooth muscular cells, and macrophages. Modified low-density lipoproteins (LDL) and cytokines, in turn, can provoke ER stress through different processes. The signaling cascades involved in ER stress initiation are complex and linked to other cellular processes, such as lysosomal biogenesis and functioning, autophagy, mitochondrial homeostasis, and energy production. In this review, we discuss the underlying mechanisms of ER stress formation and the interplay of lipid accumulation and pro-inflammatory response. We will specifically focus on macrophages, which are the key players in maintaining chronic inflammatory milieu in atherosclerotic lesions, and also a major source of lipid-accumulating foam cells.

Immunosuppressive network promotes immunosenescence associated with aging and chronic inflammatory conditions

“…There are significant alterations in the functions of autophagy, endoplasmic reticulum (ER), and mitochondria leading to cellular senescence displaying oxidative stress and disturbances in energy metabolism and protein homeostasis, although senescent cells remain metabolically active. There is robust evidence that the functions of autophagy [ 56 , 61 – 63 ], ER [ 64 , 65 ], and mitochondria [ 60 , 63 , 66 ] are disturbed in senescent mouse and human immune cells (Table 1 ). Currently, it is not known which of these three organelles is driving the senescence process, in either non-immune or immune cells.…”

The G2A Receptor Deficiency Aggravates Atherosclerosis in Rats by Regulating Macrophages and Lipid Metabolism

“…However, there may be other pathways or components involved. As shown in Figure 7 , G2A deficiency-induced elevation in LDL and ox-LDL intake leads to lipid accumulation in macrophages, which may cause activation of the ER stress-mediated pathway and promote apoptosis ( Chistiakov et al, 2016 ; Sukhorukov et al, 2020 ). The increased accumulation of apoptotic cells further enhanced lesion development and macrophage content.…”

Transthyretin: From Structural Stability to Osteoarticular and Cardiovascular Diseases

“…Atherosclerosis is a chronic inflammatory disease linked to oxidative and ER stresses [ 214 ]. In the early stages of atherogenesis, the enzymes involved in nonoxidative LDL modification (including plasmin, MMT-2, and MMT-9) are activated, initiating the cascade of reactions promoting the development of atherosclerosis [ 186 , 215 ].…”