Gene regulation in psoriatic keratinocytes: microRNAs and cytokine responses

Abstract: Psoriasis is the most common chronic skin inflammation in adults which affects 2-4% of the world population. Keratinocytes are the key structural cells in epidermis which hyper-proliferate and undergo aberrant differentiation in psoriasis. Keratinocyte-derived cytokines and chemokines are essential in maintaining the vicious auto-inflammatory loop in psoriasis. MicroRNAs (miRNAs) are small RNAs (22-25 nucleotides) which regulates gene expression at the post-transcriptional level. In this thesis, we explored the functional role of miRNAs/ cytokine networks in psoriasis. Paper I: A strong protective association of SNP (rs2910164-CC) of miR-146a to early onset of psoriasis was observed in HLA-C'06-negative patients. In addition, miR-146a deletion in mice led to earlier onset, more severe inflammation and impaired healing of imiquimod-induced psoriasis-like skin inflammation. Therapeutically, miR-146a mimic injection prevented psoriasiform skin-inflammation in WT mice, suggesting an anti-inflammatory role of miR-146a. Paper II: Here we explored the landscape of miRNAs in psoriatic keratinocytes. We identified several miRNAs, which were not identified in psoriasis before and their expression was altered in keratinocyte. In addition, upregulation of miR-1307-3p and human-specific miR-941 was validated with qRT-PCR. Paper III: MiR-149 was found to be downregulated in psoriatic keratinocytes compared to keratinocytes from non-lesional or healthy skin. In vitro studies revealed that the downregulation of miR-149 is mediated by IFN-γ/JAK/STAT axis. Functionally, miR-149 targeted the inflammatory and JAK/STAT pathway genes in resting as well as in IFN-γ treated keratinocytes. Moreover, miR-149 inhibition potentiated IFN-γ responses in keratinocytes. Paper IV: Here we outlined a new mode of action of tofactinib, a JAK inhibitor with effects on psoriasis in clinical trials. We showed that JAK proteins that are targets of tofacitinib are expressed by keratinocytes and tofacitinib had a robust impact on IL-22- regulated transcriptome in keratinocytes. Our results imply that effects of tofacitinib are not just limited to T-cells as previously thought but can also be observed in keratinocytes.

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