Oxidative Stress and Lipid Mediators Modulate Immune Cell Functions in Autoimmune Diseases

Abstract

Autoimmune diseases, including psoriasis, systemic lupus erythematosus (SLE), and rheumatic arthritis (RA), are caused by a combination of environmental and genetic factors that lead to overactivation of immune cells and chronic inflammation. Since oxidative stress is a common feature of these diseases, which activates leukocytes to intensify inflammation, antioxidants could reduce the severity of these diseases. In addition to activating leukocytes, oxidative stress increases the production of lipid mediators, notably of endocannabinoids and eicosanoids, which are products of enzymatic lipid metabolism that act through specific receptors. Because the anti-inflammatory CB2 receptors are the predominant cannabinoid receptors in leukocytes, endocannabinoids are believed to act as anti-inflammatory factors that regulate compensatory mechanisms in autoimmune diseases. While administration of eicosanoids in vitro leads to the differentiation of lymphocytes into T helper 2 (Th2) cells, eicosanoids are also necessary for the different0iation of Th1 and Th17 cells. Therefore, their antagonists and/or the genetic deletion of their receptors abolish inflammation in animal models of psoriasis-RA and SLE. On the other hand, products of non-enzymatic lipid peroxidation, especially acrolein and 4-hydroxynonenal-protein adducts, mostly generated by an oxidative burst of granulocytes, may enhance inflammation and even acting as autoantigens and extracellular signaling molecules in the vicious circle of autoimmune diseases.

Keywords: ROS; endocannabinoids; immunity; lipid mediators; oxidative stress; prostaglandins; psoriasis; psoriatic arthritis; rheumatoid arthritis; systemic lupus erythematosus.

Figure 1

Cellular interactions in psoriasis. Psoriasis is characterized by abnormal interactions between leukocytes. Overactivation of dendritic cells leads to polarization of T lymphocytes into T helper 1 (Th1) and in consequence higher levels of pro-inflammatory factors produced by these cells, which cause proliferation of keratinocytes. Activation of granulocytes during psoriasis is important for the progression of inflammation and oxidative stress.

Figure 2

Cellular interactions in lupus erythematosus (SLE) and rheumatoid arthritis (RA). SLE and RA are characterized by abnormal interactions between leukocytes. Overactivation of dendritic cells leads to higher activation of different subpopulations of T lymphocytes, and in consequence, to higher levels of pro-inflammatory molecules produced by these cells. Moreover, Th2 activates B cells, which leads to the production of autoantibodies that bind to the self-antigens, in consequence leading to the destruction of tissues and further activation of the immune system.

Figure 3

Influence of reactive oxygen species (ROS) and lipid mediators on immune cell interactions in psoriasis.

Figure 4

Influence of reactive oxygen species and lipid mediators on immune cell interactions in SLE and RA.

Figure 5

The most important lipid derivatives are generated from arachidonic acid in enzyme-dependent pathways and their receptors. Abnormal lipid metabolism is observed during oxidative stress. Non-enzymatic modifications involve the fragmentation and cyclization of lipids, leading to the formation of reactive aldehydes and isoprostanes, respectively. On the other hand, endocannabinoids and prostanoids are generated through the enzymatic pathway. These compounds affect cell functions by activating different receptors. Importantly, one compound may act on different receptors, while one receptor can be activated by different compounds.