Investigation of combined therapeutic activities of bergenin and mesenchymal stem cells in experimental psoriasis model

Psoriasis is a chronic autoimmune inflammatory disease characterized by epidermal hyperplasia and inflammation due to keratinocyte-immune cell interactions. Current therapies, while symptom-alleviating, may cause severe side effects. Dysregulation of NLRP3 inflammasome activation and Nrf2/KEAP1/SIRT1 signaling exacerbates psoriasis severity, highlighting the need for novel treatments. In this study, a translational treatment strategy was targeted with the combination of anti-inflammatory bergenin (BER) and immunosuppressive mesenchymal stem cells (MSCs). This study aimed to elucidate the therapeutic potential of combining BER and MSCs in an imiquimod (IMQ)-induced psoriasis mouse model, focusing on the NLRP3 inflammasome and the Nrf2/Keap1/SIRT1 axis. 48 BALB/c mice were divided into eight groups: control, serum physiological+Vaseline (SF+VAS), BER, MSCs, IMQ, IMQ+BER, IMQ+ MSCs, and combined. After inducing a psoriasis model with IMQ on the back and ear skin for seven days, disease severity and extent were assessed using the PASI. Histopathological analyses evaluated skin and spleen changes, while stereological methods measured volume densities in the epidermis/dermis. Immunoreactive intensities of Ki-67, NLRP3 inflammasome complex, Nrf2, Keap1, and SIRT1 were evaluated by ImageJ. TNF-α, IL-1β, IL-17A, IL-6, IL-22, and IL-23 levels were measured by ELISA. Our data showed that compared to the IMQ, BER, MSCs, and combined treatments: i) PASI score and epidermal thickness; ii) attenuated hyper/parakeratosis and Munro micro abscess formation; iii) reduced immune cell infiltration and vascularization; iv) decreased epidermal/dermal volume density; and v) significantly reduced splenomegaly, extramedullary hemopoiesis, and white pulp increase in the spleen. BER, MSCs, and combined treatments significantly decreased the immunoreactivity intensities of Ki-67, NLRP3, ASC, Caspase-1, IL-1β, and Nrf2, Keap1, cytokine levels, and significantly increased SIRT1 expressions compared to the IMQ. Our results show that BER, MSCs, and combined treatments suppress NLRP3 inflammasome activation, modulate the KEAP1/NRF2 signaling pathway, and alleviate psoriasis pathogenesis by increasing SIRT1 activation. These findings suggest that BER combined with the MSCs therapy may be a potential novel therapeutic strategy in psoriasis. Keywords: Bergenin, Mesenchymal stem cell, NLRP3 inflammasome, Nrf2/Keap1/SIRT1 axis, Psoriasis