TAZ deficiency exacerbates psoriatic pathogenesis by increasing the histamine-releasing factor.

BACKGROUND: Transcriptional coactivator with PDZ-biding motif (TAZ) is widely expressed in most tissues and interacts with several transcription factors to regulate cell proliferation, differentiation, and death, thereby influencing organ development and size control. However, very little is known about the function of TAZ in the immune system and its association with inflammatory skin diseases, so we investigated the role of TAZ in the pathogenesis of psoriasis. RESULTS: Interestingly, TAZ was expressed in mast cells associated, particularly in lysosomes, and co-localized with histamine-releasing factor (HRF). TAZ deficiency promoted mast cell maturation and increased HRF expression and secretion by mast cells. The upregulation of HRF in TAZ deficiency was not due to increased transcription but to protein stabilization, and TAZ restoration into TAZ-deficient cells reduced HRF protein. Interestingly, imiquimod (IMQ)-induced psoriasis, in which HRF serves as a major pro-inflammatory factor, was more severe in TAZ KO mice than in WT control. HRF expression and secretion were increased by IMQ treatment and were more pronounced in TAZ KO mice treated with IMQ. CONCLUSIONS: Thus, as HRF expression was stabilized in TAZ KO mice, psoriatic pathogenesis progressed more rapidly, indicating that TAZ plays an important role in preventing psoriasis by regulating HRF protein stability.

Dimeric translationally controlled tumor protein-binding peptide 2 attenuates imiquimod-induced psoriatic inflammation through induction of regulatory T cells.

Psoriasis is a chronic skin inflammation caused by a dysfunctional immune system, which causes systemic inflammation in various organs and tissues. Due to the risk of systemic inflammation and recurrence of psoriasis, it is important to identify the critical targets in the pathogenesis of psoriasis and develop targeted therapeutics. Dimerized translationally controlled tumor protein (dTCTP) promotes immune cell activation as a pro-inflammatory cytokine and plays a role in developing allergic diseases such as asthma and rhinitis. Here, we sought to explore whether dTCTP and its inhibition contributed to the development and control of imiquimod (IMQ)-induced psoriasis. Topical application of IMQ inflamed the skin of the back and ear, increased inflammatory cytokines, and decreased regulatory T cell markers. Interestingly, TCTP was significantly increased in inflamed skin and immune cells such as T cells, B cells, and macrophages after IMQ treatment and was secreted into the serum to undergo dimerization. Extracellular dTCTP treatment selectively suppressed regulatory T (Treg) cells, not other effector T helper (Th) cells, and increased M1 macrophages. Moreover, dTCTP-binding peptide 2 (dTBP2), a dTCTP inhibitor peptide, effectively attenuated the systemic inflammatory responses, including Th17 cell response, and alleviated psoriatic skin inflammation. dTBP2 blocked dTCTP-mediated Treg suppression and stimulated the expression of Treg cell markers in the spleen and inflammatory skin lesions. These results suggest that dTCTP dysregulated immune balance through Treg suppression in psoriatic inflammation and that functional inhibition of dTCTP by dTBP2 maintained immune homeostasis and attenuated inflammatory skin diseases by expanding Treg cells.

dTBP2 attenuates severe airway inflammation by blocking inflammatory cellular network mediated by dTCTP.

Dimeric translationally controlled tumor protein (dTCTP), also known as histamine-releasing factor, amplifies allergic responses and its production has been shown to increase in inflammatory diseases such as allergic asthma. Despite the critical role of dTCTP in allergic inflammation, little is known about its production pathways, associated cellular networks, and underlying molecular mechanisms. In this study, we explored the dTCTP-mediated inflammatory networks and molecular mechanisms of dTCTP associated with lipopolysaccharides (LPS)-induced severe asthma. LPS stimulation increased dTCTP production by mast cells and dTCTP secretion during degranulation, and extracellular dTCTP subsequently increased the production of pro-inflammatory molecules, including IL-8, by airway epithelial cells without affecting mast cell activation. Furthermore, dimeric TCTP-binding peptide 2 (dTBP2), a dTCTP inhibitor peptide, selectively blocked the dTCTP-mediated signaling network from mast cells to epithelial cells and decreased IL-8 production through IkB induction and nuclear p65 export in airway epithelial cells. More importantly, dTBP2 efficiently attenuated LPS-induced severe airway inflammation in vivo, resulting in decreased immune cell infiltration and IL-17 production and attenuated dTCTP secretion. These results suggest that dTCTP produced by mast cells exacerbates airway inflammation through activation of airway epithelial cells in a paracrine signaling manner, and that dTBP2 is beneficial in the treatment of severe airway inflammation by blocking the dTCTP-mediated inflammatory cellular network.