IL-17A/IL-17C/TNFa suppression of TCF4 promotes a ZC3H12A-mediated self-sustaining inflammatory feedback cycle involving IL-17RA/IL-17RE epidermal signaling

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Presentation Time: 05:15 PM - 05:30 PM
Abstract ID: 5229 - B

Presenting Author:
Nicole L Ward , Professor of Dermatology and Pathology, Molecular Biology and Immunology at Vanderbilt Univ. Med. Ctr., Case Western Reserve Univ.

Abstract:

IL-17C is an epithelial cell-derived cytokine that increases in inflammatory skin diseases however the mechanisms regulating IL-17C expression remain unclear. IL17C promoter analysis identified TCF4 as a putative regulator of IL-17C. Examination of inflamed skin from psoriasis and atopic dermatitis patients revealed a negative correlation between TCF4 and IL17C and IL-17C, IL-17A and/or TNFa stimulation of human keratinocytes (KCs) decreased TCF4, which occurred in an IL-17RA/RE dependent manner. Depletion of TCF4 in KCs using siRNA increased IL17C and ZC3H12A and IL-17C stimulation of KCs further increased ZC3H12A and NFBIZ in an IL-17RE/RA-dependent manner.  SiRNA knockdown of ZC3H12A in KCs confirmed its importance in promoting inflammation, including further regulation of NFKBIZ.  Next, using a dermatitis mouse model we identified decreases in epidermal TCF4, increases in IL-17C and Zc3h12a, and determined that genetic elimination of Il17re or Il17ra eliminated the skin phenotype, increased TCF4 and decreased Zc3h12a, IL-17C and IL-17A. Conversely, topical Tcf4 silencing worsened the skin phenotype and increased Il17c and Zc3h12a. These findings demonstrate that IL-17C-IL-17A-TNFa decrease TCF4 which negatively regulates IL-17C and ZC3H12A expression in KCs and that IL-17C further promotes the expression of ZC3H12A and NFKBIZ in an IL-17RA/RE-dependent manner to promote inflammation that becomes self-sustaining.