Role of PSTPIP1 in a Mouse Model of PAPA Syndrome

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DESCRIPTION (provided by applicant): Pyrogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome, previously referred to as streaking leucocyte factor disease, is a rare autosomal dominant autoinflammatory disorder characterized by sterile inflammation of the joints and skin, arthritis and severe acne. The disease is strongly associated with two defined mutations in the PSTPIP1 gene. The associated arthritis often leads to joint destruction and debilitation. Neither PAPA syndrome related pyoderma gangrenosum nor acne respond well to conventional therapy, including steroids or high dose antibiotics, although there are now reports of successful therapy using human interleukin (IL)-1 receptor antagonist, suggesting a causal role for IL-1?. In vitro studies have shown that dysregulation of caspase-1 activating inflammasomes may contribute to the pathogenesis. It is thought that mutant PSTPIP1 multimerizes spontaneously, subsequently binds PYRIN, and activates caspase 1 via the adapter ASC. However, little is known about the normal physiological function of PSTPIP1 and nor how mutant PSTPIP1 proteins cause inflammasome activation. To elucidate the function of PSTPIP1, we have established a conditional allele of the Pstpip1 encoding gene in mice. Ablation of PSTPIP1 expression can be achieved in a conditional manner. Using this conditional knockout strain, we will test the importance of PSTPIP1 in the process of inflammasome activation both in vivo and in vitro. Biochemical studies as well as infectious challenges of cells derived from these mice, or the mice themselves, should shed light on the normal physiological role of PSTPIP1. In addition, we have also generated mouse strains in which ectopic expression of mutants of PSTPIP1 that correspond to the human mutations can be induced in a tissue or cell lineage specific manner using the Rosa 26 locus targeting technology. We hypothesize that ectopic expression of mutant PSTPIP1 will lead to PAPA-like disease conditions in these mice. By analyzing the resultant phenotypes in the transgenic mice, we expect to gain insights into how mutant PSTPIP1 causes PAPA syndrome. In addition, we believe the proposed research will provide insights into the pathophysiological processes of autoinflammatory diseases and lead to new clues in designing therapies for immune disorders.