SIRT1-STAT3 In Psoriasis:Mechanism And Treatment

Psoriasis is a common chronic immune-mediated disease.The etiology of psoriasis has a large hereditary component,and has been linked with environmental,and metabolic disease.Abnormal activation of STAT3 plays a crucial role in psoriasis pathogenesis.The level of activated STAT3 increases in human psoriatic plaques,and transgenic mice with keratinocytes constitutively expressing activated STAT3 develop a typical psoriatic phenotype on the skin.However,the reason for the persistent activation of STAT3 in psoriasis remains to be investigated.SIRT1 has been proven a key metabolic sensor that directly link environmental signals to mammalian metabolic homeostasis and stress response.Caloric restriction promotes SIRT1 activity.It is also reported that SIRT1 inhibited proliferation and promotes differentiation in ketatinocytes.In the previous study,we have found that SIRT1 inhibits STAT3 phosphorylation and functions on gluconeogenesis in the liver,through SITR1-mediated deacetylation of the key STAT3 lysine sites,which can be a response to nutrient change.We hypothesized that SIRT1 might participate in the persistent activation of STAT3,which triggers the development of psoriasis,and energy metabolism could influence the development of psoriasis via SIRT1-STAT3.In this study,we detected that SIRT1 is reduced in the lesions of psoriatic patients,compared with the healthy individuals.We found a direct interaction between SIRT1 and STAT3 in the human keratinocytes and mouse epithelia.We show that cytokines stimulated STAT3 activation in human keratinocytes is down-regulated by SIRT1.SIRT1 can negatively regulate the STAT3-related phenotypes in keratinocytes,including excessive proliferation and Keratin 17 expression.Using the imiquimod(IMQ)-induced psoriatic mouse model,we demonstrated that SIRT1 activator meliorated the psoriasis-like lesions either in the clinical or the histopathologic manifestation of the skin,via down-regulate the STAT3 activation;conversely,SIRT1 inhibitor EX527 treatment aggravated the skin lesions.To study effect of energy metabolism on the development of psoriasis,we used a calorie restriction(CR)mouse model and a dietary induced obesity(DIO)mouse model.After the imiquimod induction,we found a more milder psoriasis-like lesion on the back skin of the CR mouse,with reduced Ki-67 and Keratin 17 expression,compared with those taking up normal dietary(C-I).By contrast,the DIO mouse showed a more severe skin lesion,with increased Ki-67 and Keratin 17 expression.However,the differences between DIO and C-I mouse have no statistical significance.Furthermore,we found SIRT1 expression increased,Ac-STAT3 and PY-STAT3 decreased in the epithelia of the mouse back skin in the CR group.In contrast,SIRT1 decreased and PY-STAT3 increased in the epithelia of the mouse back skin in the DIO group.It suggested that SIRT1-STAT3 may play an important role in energy metabolism and psoriasis.In addition,we found calorie restriction could maintain the T cell balance,and reduced the infiltration of Th cells to the skin lesion.It may be another mechanism to explain the reason that CR could inhibit psoriasis.These data suggested that SIRT1 may be an effective therapeutic target for psoriasis treatment.