S100A8/A9 contributes to inflammatory exacerbations in neutrophils and monocytes from PAMI syndrome

Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated myeloid-related proteinemia inflammatory (PAMI) syndrome is a monogenic autoinflammatory disease characterized by progressive arthritis with neutrophilic infiltration, cytopenia, and high serum S100A8/A9 and zinc. The molecular pathophysiology of PAMI caused by particular variants of the PSTPIP1 gene, such as PSTPIP1 E250K, is still unknown, and targeted therapy based on the pathogenesis has not been developed. We established an analytical model of neutrophils and monocytes/macrophages using induced pluripotent stem cells harboring the PAMI variant and another PSTPIP1 E250Q variant observed in PSTPIP1-related disorders with milder phenotypes. Using the model cells, we demonstrated increased production of reactive oxygen species, inflammatory cytokines, S100A8/9, increased cell death in the E250K neutrophils, and increased production of cytokines and abnormal phenotype of E250K monocytes/macrophages. With these model cells, we delved into the molecular basis of the hyperinflammation and pronounced S100A8/A9 production. Our data revealed that S100A8/A9 was at the center of hyperinflammation in PAMI syndrome and its deletion can reverse functional and molecular abnormalities in the phagocytes.