The immunity is essential for host defense against the invasion of foreign pathogens. The Th17 pathway is activated by dynamic interplays among epithelial cells, T cells, dendritic cells. Under normal physiological conditions, Th17 pathway is tightly controlled to prevent chronic inflammation. However, constitutive Th17 activation is a common pathological feature in many chronic inflammatory diseases including rheumatoid arthritis and psoriasis. So far the molecular basis of constitutive Th17 activation in Th17 inflammatory diseases remains largely unknown. In this study, we have provided experimental evidence to suggest that the inactivation of PIASy contributes to constitutive Th17 activation. PIASy-deficient mice developed psoriasis-like phenotypes and showed increased Th17 cytokine expression in response to topical imiquimod treatment. More importantly, PIASy deficiency resulted in robust expression of IL-23 from keratinocytes in response to the treatment of TNF? and IL-17A. This is the first time to demonstrate that human psoriatic keratinocytes produce robust IL-23 in response to TNF? and IL-17A. As IL-23 is essential for Th17 activation, IL-23 induction by Th17 cytokines in keratinocytes provides a molecular basis for forming a positive regulatory loop of Th17 activation through IL-23 overproduction from psoriatic keratinocytes and IL17/TNF? cytokine overproduction from Th17 T cells. Biochemically, we have identified NF?B and STAT3 as the targets negatively regulated by PIASy. As NF?B and STAT3 are the major contributors in the inflammation circuitry of psoriasis, I hypothesize that inactivation of PIASy contributes to sustained Th17 activation in psoriasis. This hypothesis will be tested by 1) Establish the clinical relevance of PIASy inactivation and its correlation with IL-23 expression and the activation of NF-kB and STAT3 in human psoriasis~ 2) Defining the functional role of PIASy in IL23 expression from keratinocytes~ 3) Defining the functional role of PIASy in Th17 T cells differentiation and IL17 expression from Th17 T cells. The analysis of the PIASy molecular pathway in Th17 regulation will not only enable us to understand the molecular basis of aberrant inflammation in psoriasis, but also provide novel strategies for psoriasis prognosis, prevention and therapy.
In psoriasis, a chronic inflammatory skin disease with genetic predisposition affecting approximately 2% of the US population, there is a dynamic interaction between keratinocytes (the most common type of cell found in the outermost layer of skin) and T lymphocytes (a type of white blood cell). We found that dysfunctional PIASy, an enzyme that represses the transcription of genes controlling inflammation, causes keratinocytes to produce IL-23 cytokine in response to two other cytokines produced by T lymphocytes, IL-17 and TNF? which contributes to a vicious circle of skin inflammation. The aims of this study are to define th molecular basis of PIASy inactivation in psoriasis and dissect the functional role of PIASy inactivation in the development of skin inflammation.
| Liu, Yuangang; Wang, Zhiping; De La Torre, Rachel et al. (2017) Trim32 Deficiency Enhances Th2 Immunity and Predisposes to Features of Atopic Dermatitis. J Invest Dermatol 137:359-366 |
