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

• Applicant: Dr. Athanasios Stratis
• Subject Area: Rheumatology
• Term: from 2010 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 170443123

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.

• DFG Programme: Research Grants