Psoriatic-Arthritis (PsA) is a type of inflammatory chronic arthritis with a seronegative spondyloarthropathy and associated psoriasis. The Danger-Associated Molecular Pattern molecules (DAMPs) S100A8 and S100A9 are both antimicrobial proteins with chemotactic activity and are the most abundant DAMPs expressed during many inflammatory disorders. The expression of the S100A8/S100A9-complex is highly elevated in psoriasis and psoriatic arthritis.Background
However, the mechanisms that regulate S100A8/S100A9-complex-activities are poorly understood, which has led us to examine the role of S100A8 and S100A9 under chronic inflammatory conditions.Material and methods
We crossed S100A9-deficient mice with TTP (tristetraprolin)-deficient mice into a systemic inflammatory model featuring high levels of TNF with an arthritic joint destruction phenotype. Disease progression in TTP-/- x S100A9-/- mice was analysed by immunostaining, immunohistochemistry and the adapted PASI-score. To neutralise TNF in TTP-/- x S100A9-/- mice we used an aTNF-inhibiting monoclonal antibody already in clinical use for therapy of arthritis and psoriasis. To measure altered protein levels we used Western blot analysis. Primary keratinocytes were isolated of the skin from newborn mice and infected with E.coli isolated from the faeces of mice.Results
TTP/S100A9 deficiency led to highly elevated levels of the S100A9 complex partner S100A8 in the epidermis and to a severe psoriatic phenotype of TTP-/- x S100A9-/- mice. Furthermore the mice showed an accelerated course of arthritis compared to TTP-/- mice, including increased articular cartilage loss and bone destruction. Inhibition of TNF by application of anti-TNF clearly reduced the psoriatic phenotype of TTP-/- x S100A9-/- mice. Additionally, the reduction of the environmental bacterial levels led to a milder phenotype and decelerated pathogenesis. The in vitro infection of isolated keratinocytes with isolated E.coli resulted in a high expression of S100A8.Conclusions
The data reveal that the S100A8/S100A9-complex acts not only as a systemic danger signal molecule, but is also TNF dependent and is essential for the regulation of inflammation. The loss of S100A9 led to a disregulated inflammatory response and this to a severe psoriasis with enhanced cartilage and bone destruction. Furthermore, an exogenic bacterial factor, such as E. coli, is also demonstrated to be important in the activation of the disease.