Cyr61 Aggravates Epidermal Hyperplasia Via Regulating Keratin Expression In Psoriasis Pathogenesis

Psoriasis is a common chronic skin disease characterized by epidermal hyperplasia, parakeratosis and inflammation. Although the pathogenesis is unc lear, epiderma l hyperplasia mediate d by keratinocyte(KC) activation is a key pathologica l process during psoriasis de velopment. Keratins are responsible for the keratinocytes activation. According to the effect on KC biological characteristics, keratins can be divided into three subunits: the first is the proliferative keratins, suc h as K5, K14, mainly expressed in the basa l layer cells; the second is differentiated keratins, such as K1 and K10, these keratins expression mediate d KC differentiation and migrating to the stratum corne um; the third is the activated keratins, suc h as K6, K16 and K17, which only expressed in injure d or stimulated KC. Keratins expression is mediated by inflammatory cytokines and growth factors. In psoriasis, increased expression of pro-inflammatory cytokines such as IL-1 and TNF-α induced activated keratins up-regulation, which led to the keratinoc yte hyperplasia. Thus, inhibiting the inflammatory cytokines expression is the ma in treatme nt strategy to reduce the epiderma l hyperplasia and inflammation for psoriasis.Cysteine-rich 61(Cyr61) is a secreted extracellular matrix prote in. Our group first found that Cyr61, acts as a nove l pro-infla mmatory factor, contributes to the hyperplasia of synovia l lining cells and inflammation by increasing IL-6 and IL-8 expression in rheumatoid arthritis. Moreover, our recent studies found that the expression of Cyr61 was up-regulated in lesion skin of psoriasis patients, and Cyr61 could up-regulate K6 expression, which led to the hyperactivation of KC. But whether Cyr61 plays any role in regulating other keratins expression is still unexplored.In this study, we first examine d the Cyr61 and keratins expression profile in skin lesions of psoriasis patients and IL-23/imiquimod(Imiquimod, IMQ) induced psoriasis-like mouse mode l. And we also analyzed the correlation between them. The results showed that the expression of Cyr61 and activated keratin K6 and K16 showed a significant positive corre lation, while the expression of Cyr61 and proliferative keratin K5, K14 and differentiated keratin K1, K10 showed a negative corre lation.Then, we studied the regulation role of Cyr61 on these three types of keratins in vitro. When added Cyr61 prote in into KCs, we found Cyr61 improved K6 expression, and inhibited the differentiated keratin K5 and K14 expression directly; a nd interference of endogenous Cyr61 expression in KC induced impired K6 expression, while increased K5, K14 and differentiated keratin K1, K10 expression.These results suggest that Cyr61 indeed increased K6 expression and KC activation. It has been reported that KC activation is ma inly driven by IL-1: IL-1 can increased K6 and K16 expression, leading to KC activation. Further, TNF-α maintains the KC activation, which led to the occurrence of psoriasis. We have found that in rheumatoid arthritis, Cyr61 promoted the synthesis of pro IL-1β in synovial cells, and with the assistance of ATP, mature IL-1β secreted into the supernatant. Therefore, we also discussed the role of Cyr61 in regulating IL-1β expression in KCs. In vitro studies revealed that, Cyr61 bind to integrin receptors α6β1 on KC surface, and start the downstream p38 MAPK signa ling pathway to increase the IL-1β expression. These results indicate that Cyr61 could not only regulate K6 expression directly, but also might promote K16 expression via up-regulating IL-1β expression.Furthermore, we blocked Cyr61 expression by lentivira l vector expressing short hairpin RNA(shRNA) or Cyr61 monoc lona l neutralizing antibody in IL-23/IMQ-induced psoriasis-like skin lesions and explore d the role of Cyr61 on regulation of keratins expression and epiderma l hyperplasia. We found that K6 and K16 expression reduced after blocking Cyr61 expression, so that inhibited the activation of KC and re lieved the epiderma l hyperplasia.Taken together, in current study, using primary culture of keratinocytes, psoriasis-like mice model, lentivira l vector and neutra lizing antibody, we aim to fully understand the role of Cyr61 on regulating keratins expression involved in the epiderma l hyperplasia. We state that Cyr61 regulates K6 expression directly, which aggravates KC activation; on the other hand, Cyr61 might also increase K16 expression through up-regulation IL-1β expression, contributes to the epidermal hyperplasia and inflammation of psoriasis. This suggests that Cyr61 plays a critical role in pathogenesis of psoriasis. Furthermore, blocking Cyr61 function can effectively suppresses skin lesion and inflammation, supplying the evidence for that targeting Cyr61 may represent a new potent strategy in psoriasis treatment.