Abstract
Psoriasis, a multisystem chronic disease characterized by abnormal keratinocyte proliferation, has an unclear pathogenesis where systemic inflammation and oxidative stress play mutual roles. Dermal fibroblasts, which are known to provide a crucial microenvironment for epidermal keratinocyte function, represented the selected experimental model in our study which aimed to clarify the potential role of SIRT1 in the pathogenetic mechanisms of the disease. We firstly detected the presence of oxidative stress (lipid peroxidation and total antioxidant capacity), significantly reduced SIRT1 expression level and activity, mitochondrial damage and apoptosis (caspase-3, -8 and -9 activities) in psoriatic fibroblasts. Upon SIRT1 activation, redox balance was re-established, mitochondrial function was restored and apoptosis was no longer evident. Furthermore, we examined p38, ERK and JNK activation, which was strongly altered in psoriatic fibroblasts, in response to SIRT1 activation and we measured caspase-3 activity in the presence of specific MAPK inhibitors demonstrating the key role of the SIRT1 pathway against apoptotic cell death via MAPK modulation. Our results clearly demonstrate the involvement of SIRT1 in the protective mechanisms related to fibroblast injury in psoriasis. SIRT1 activation exerts an active role in restoring both mitochondrial function and redox balance via modulation of MAPK signaling. Hence, SIRT1 can be proposed as a specific tool for the treatment of psoriasis.
Highlights
Psoriasis, a chronic, inflammatory multisystemic disease affecting 2–3% of the world population, is characterized by abnormal keratinocyte proliferation resulting in the formation of raised, itchy and well-demarcated erythematous lesions on the skin
We focused on dermal fibroblasts which exert specific functions in the microenvironment of epidermal keratinocytes and, together with infiltrating PMNs, induce a marked redox imbalance in psoriatic derma by extensively producing reactive oxygen species (ROS), such as superoxide and H2O2, and displaying a significant role in the anomalous keratinocyte growth which characterizes psoriasis [5]
Sirtuin 1 (SIRT1) activity (Figure 1B) in psoriatic fibroblasts exhibited a significant decrease in comparison with healthy cells (306 ± 99 vs. 855 ± 188, p < 0.01)
Summary
A chronic, inflammatory multisystemic disease affecting 2–3% of the world population, is characterized by abnormal keratinocyte proliferation resulting in the formation of raised, itchy and well-demarcated erythematous lesions on the skin. The molecular features and the factors responsible for the complex interactions between dermal stromal cells and epidermal keratinocytes in both physiologic and pathologic conditions are still to be elucidated. On these bases, we focused on dermal fibroblasts which exert specific functions in the microenvironment of epidermal keratinocytes and, together with infiltrating PMNs, induce a marked redox imbalance in psoriatic derma by extensively producing reactive oxygen species (ROS), such as superoxide and H2O2, and displaying a significant role in the anomalous keratinocyte growth which characterizes psoriasis [5]. For the first time, we investigated in primary fibroblasts from lesional psoriatic skin, the possible involvement of SIRT1 in MAPK pathways
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
