Mutation of Mouse MAYP/PSTPIP2 Causes a Macrophage Autoinflammatory Disease.

Macrophage actin-associated tyrosine phosphorylated protein (MAYP), a Pombe Cdc15 Homology (PCH) family protein also known as proline serine threonine phosphatase-interacting protein 2 (PSTPIP2), is involved in the regulation of macrophage motility (Chitu et al., 2005). Mutations in a closely related gene, PSTPIP1/CD2 binding protein 1 (CD2BP1) cause a dominantly inherited autoinflammatory disorder known as PAPA syndrome. A mutant mouse obtained by chemical mutagenesis exhibited an autoinflammatory disorder characterized by macrophage infiltration and inflammation leading to osteolysis and necrosis in paws and necrosis of ears. Positional cloning of this recessive mutation, termed Lupo, identified a T to A nucleotide exchange leading to an amino acid substitution (I282N) in the sequence of MAYP. Mayp^Lp/Lp disease was transferable by bone marrow transplantation and developed in the absence of lymphocytes. Consistent with the involvement of macrophages, lesion development could be prevented by the administration of chlodronate liposomes. MAYP is expressed in monocytes/macrophages and a Mac1+ sub-fraction of granulocytes. LPS stimulation increases its expression in macrophages. Due to instability of the mutant protein, MAYP expression is reduced 3-fold in Mayp^Lp/Lp macrophages and upon LPS stimulation does not rise above the level of unstimulated wt cells. Mayp^Lp/Lp mice expressed elevated circulating levels of IL-4, Rantes, TGF-beta and MCP-1 and in vitro their macrophages exhibit altered cytokine production. These studies suggest that MAYP plays an anti-inflammatory role in macrophages.