Pathophysiological Alterations of Redox Signaling and Endocannabinoid System in Granulocytes and Plasma of Psoriatic Patients

Abstract

Inflammatory granulocytes are characterized by an oxidative burst, which may promote oxidative stress and lipid modification both in affected tissues and on a systemic level. On the other hand, redox signaling involving lipid peroxidation products acting as second messengers of free radicals play important yet not fully understood roles in the pathophysiology of inflammation and various stress-associated disorders. Therefore, the aim of this study was to evaluate the onset of oxidative stress and alterations of enzyme-dependent lipid metabolism resulting from redox imbalance in granulocytes and plasma obtained from patients with psoriasis vulgaris or psoriatic arthritis in comparison to the healthy subjects. The results obtained revealed enhanced activity of pro-oxidant enzymes nicotinamide adenine dinucleotide phosphate (NADPH) and xanthine oxidases in granulocytes with a decrease of enzymatic and non-enzymatic antioxidants in the plasma of psoriatic patients. The nuclear factor erythroid 2–related factor 2 (Nrf2) and its regulators were increased in both forms of psoriasis while heme oxygenase 1 levels were increased only in psoriasis vulgaris. The redox imbalance was associated with decreased levels of phospholipids and of free polyunsaturated fatty acids but with enhanced activity of enzymes involved in lipid metabolism (phospholipase A2, acetylhydrolase PAF, cyclooxygenases 1 and 2) and increased lipid peroxidation products 4-hydroxynonenal, isoprostanes, and neuroprostanes. Increased endocannabinoids and G protein-coupled receptor 55 were observed in both forms of the disease while expression of the cannabinoid type 1 receptor (CB1) was increased only in patients with psoriatic arthritis, which is opposite to the cannabinoid type 2 receptor. This receptor was increased only in psoriasis vulgaris. Changes in protein expression promoted the apoptosis of granulocytes by increased caspases mainly in psoriasis vulgaris. This study indicates that inhibition of the Nrf2 pathway in psoriatic arthritis promotes a redox imbalance. In addition, increased expression of CB1 receptors leads to increased oxidative stress, lipid modifications, and inflammation, which, in turn, may promote the progression of psoriasis into the advanced, arthritic form of the disease.

Cannabidiol Effects on Phospholipid Metabolism in Keratinocytes from Patients with Psoriasis Vulgaris

“…The formation of 4-HNE-protein adducts in psoriatic keratinocytes has already been demonstrated in proteomics studies, especially in the context of proteins involved in the antioxidant response [78]. The intensification of the lipid peroxidation process was also observed in the blood cells and plasma of patients with psoriasis vulgaris [49,50], which confirms that this disease, regardless of local metabolic modifications in skin cells, is also characterized by changes in systemic metabolism. The UV irradiation of keratinocytes also enhances lipid peroxidation by increasing the level of 4-HNE-protein adducts, promoting further metabolic changes.…”

“…Although endogenous antioxidants counteract the effects of ROS overproduction, the excessively high and/or long-lasting presence of ROS in cells, such as in disease conditions, leads to oxidative stress. Recently, we have shown a shift in redox balance towards oxidative conditions with the formation of oxidative stress in plasma, lymphocytes, and granulocytes of patients with psoriasis, leading to the intensification of oxidative modifications of lipids, proteins, and other endogenous compounds [49][50][51]. Different populations of activated leukocytes infiltrating skin lesions also lead to an increase in the level of local oxidants and cause a pro-inflammatory response, as well as oxidative modifications of proteins and lipids in skin cells, especially in keratinocytes [52,53].…”

A Guide to Targeting the Endocannabinoid System in Drug Design

“…Unfortunately, its functions are not straightforward. Increased expression of CB1 was shown to promote oxidative stress and inflammation [201]. Contrarily, CB1 agonists decreased mast cell activation in vitro, exhibiting also anti-inflammatory activity in the rodent model, and are proposed as anti-inflammatory agents in psoriasis and dermatitis [202].…”

Involvement of Metabolic Lipid Mediators in the Regulation of Apoptosis

“…In addition, lipid modifications lead to the generation of lipid mediators, which-independent of ROS-cause changes such as alterations to the structure of signaling and structural proteins. These alterations can lead to metabolic dysregulation, including modification of transcription factor activity and, consequently, can promote cell death [9][10][11]. In this way, ROS may be involved in the regulation of major apoptosis signaling pathways.…”