Regulation of chronic inflammation in psoriatic-Arthritis by S100A8 and S100A9, Mechanisms and therapeutic implications.

髓系相关蛋白-14(MRP14，S100A9)是一种损伤相关分子模式(DAMP)分子，与其二聚体髓系相关蛋白-8(MRP8，S100A8)一起在许多炎症性疾病中增加，并已被证明具有促炎功能。到目前为止，MRP8和MRP14的表达被认为是密切相关的，而MRP14的缺失也被认为是导致MRP8功能敲除的原因。在这里，我们证明在炎症条件下，MRP8和MRP14具有分离的表达和功能，MRP14缺陷通过MRP8的不平衡表达促进肿瘤坏死因子α(TNFpha)依赖的炎症。在过度表达TTP-/-(Tristetraprolin)的小鼠身上，表现出轻微的皮肤炎症，MRP14的缺乏会导致一种严重的牛皮癣样皮肤病，具有人类牛皮癣的所有主要组织学特征。在这些小鼠中，牛皮癣样疾病伴随着高水平的MRP8，主要是角质形成细胞，并导致出生后2周内死亡。与TTP-/-/S100A9-/-相比，TTP-/-/S100A9-/-在银屑病发病过程中上调的效应分子包括IL-17、IL-23和IL-22的表达显著增加。在此背景下，我们目前的工作表明，S100A9-/-，TNFpha过表达小鼠(TTP-/-/S100A9-/-)银屑病表型的严重程度取决于保持笼中的E.Coli浓度。我们的结果表明，除了TNFpha和S100A8外，细菌信号也是诱导早期强烈银屑病表型所必需的。在目前的应用中，我们将研究内源性和外源性免疫抵抗激活剂如何参与银屑病或银屑病关节炎发展的潜在机制。

The myeloid-related protein-14 (MRP14, S100A9) is a damage-associated molecular pattern (DAMP) molecule that together with its dimerization partner myeloid-related protein-8 (MRP8, S100A8) is increased in many inflammatory disorders and has been shown to have proinflammatory functions. So far, the expression of MRP8 and MRP14 have been regarded as being closely related, whilst the lack of MRP14 has been considered to also result in a functional knockout of MRP8. Here, we show that under inflammatory conditions, MRP8 and MRP14 have separable expression and functions, with MRP14 deficiency promoting tumor necrosis factor alpha (TNFalpha) dependent inflammation via unbalanced expression of MRP8. In TNFalpha overexpressing TTP-/- (tristetraprolin) mice that show mild inflammation of the skin, the lack of MRP14 leads to a severe psoriasis-like skin disease with all major histological characteristics of human psoriasis. Psoriasis-like disease in these mice is accompanied by high levels of MRP8, mainly in keratinocytes, and leads to death within 2 weeks after birth. The expression of effector molecules known to be upregulated during the pathogenesis of psoriasis, including IL-17, IL-23 and IL-22 is markedly increased in TTP-/-/S100A9-/- as compared to TTP-/- mice. In this context our current work show that the severity of the psoriatic phenotype in S100A9-/-, TNFalpha overexpressing mice (TTP-/-/S100A9-/-) is dependent on the E.Coli concentration in the holding cages. Our results show that in addition to TNFalpha and S100A8, bacterial signals are also required to induce an early strong psoriatic phenotype. In the present application we will study the underlying mechanisms of how endogenous and exogenous activators of the immune resistance are involved in the development of psoriasis or psoriatic-arthritis.