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

Abstract

Inflammatory granulocytes are characterized by oxidative burst, which may promote oxidative stress and lipid modification both in affected tissues and on systemic level. On the other hand, redox signaling involving lipid peroxidation products acting as second messengers of free radicals play important, not yet fully understood, roles in 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 NADPH and xanthine oxidases in granulocytes, with a decrease of enzymatic and non-enzymatic antioxidants in plasma of psoriatic patients. The Nrf2 and its regulators were increased in both forms of psoriasis, while HO-1 levels were increased only in psoriasis vulgaris. Redox imbalance was associated with decreased levels of phospholipids and of free PUFAs, but with enhanced activity of enzymes involved in lipid metabolism (PLA2, PAF-AH COX1/2) and increased lipid peroxidation products 4-hydroxynonenal (4-HNE), isoprostanes and neuroprostanes. Increased endocannabinoids and GPR55 were observed in both forms of the disease, while expression of CB1 was increased only in pateints with psoriatic arthritis, opposite to CB2, which was increased only in psoriasis vulgaris. Protein modifications by ROS and lipid peroxidation product 4-HNE promoted apoptosis of granulocytes by increased caspases in both forms of psoriasis.This study indicates that excessive activation of granulocytes, causing oxidative stress and lipid modifications, is an important pathophysiology of psoriasis. Consequently, lower Nrf2 activity and CB2 expression may promote progression of psoriasis into advanced, arthritic form of the disease.

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

“…Autoimmune diseases are usually accompanied by metabolic changes that involve the development of pro-inflammatory processes and oxidative stress. In psoriasis, redox imbalance is observed not only in skin cells but also in plasma and blood cells, including granulocytes and lymphocytes [ 33 , 34 ]. Moreover, it has also been shown that mutations in genes encoding some antioxidants, such as paraoxonase-1, correlate with the severity of the disease [ 35 ].…”

“…Moreover, it has also been shown that mutations in genes encoding some antioxidants, such as paraoxonase-1, correlate with the severity of the disease [ 35 ]. As a result, higher levels of oxidatively modified lipids and proteins can also be observed [ 33 , 34 , 36 ]. Therefore, it has been suggested that a diet rich in antioxidants should treat psoriasis.…”

“…This leads to serious metabolic disturbances and can even lead to cell death [ 49 ]. ROS also lead to the activation of transcription factors that modulate the biosynthesis of antioxidant proteins and pro-inflammatory factors [ 33 ]. Therefore, oxidative-stress-dependent activation of transcription factors can exacerbate inflammation and activate immune cells [ 33 , 34 ].…”

“…[ 50 , 51 ]. Psoriasis, both vulgaris and arthritic, as well as SLE and RA, have higher expression of NF-κβ and TNF-α, which is the product of its activity [ 33 , 34 , 52 ]. In contrast, inhibition of TNF-α action leads to improvement of the clinical condition of patients suffering from these diseases.…”

Evaluation of changes in expression pattern of oxidative stress genes under the influence of adalimumab

“…In many cases, there is a relationship between the onset of inflammation and the occurrence of oxidative stress, which results from an increase in the number and activation of granulocytes during inflammation. Granulocytes are a source of ROS produced during the so-called respiratory burst (Ambro_ zewicz et al, 2018). TNF-α plays an important role in the pathogenesis of psoriasis, which contributes to the induction and development of inflammation or excessive proliferation of keratinocytes.…”