SPARC regulation of PMN clearance protects from pristane induced lupus and rheumatoid arthritis

Summary The secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein with unexpected immunosuppressive function in myeloid cells. We investigated the role of SPARC in autoimmunity using the pristane–induced model of lupus that, in mice, mimics human SLE. Sparc-/- mice developed earlier and more severe renal disease, multi-organs parenchymal damage and arthritis than the WT counterpart. Sparc+/- heterozygous mice showed an intermediate phenotype suggesting Sparc gene-dosage in autoimmune-related events. Mechanistically, reduced Sparc expression in neutrophils blocks their clearance by macrophages, through defective delivery of don’t eat-me signals. Dying Sparc-/- neutrophils that escape macrophage scavenging become source of autoantigens for dendritic cell presentation and are a direct stimulation for γδ-T-cells. Gene profile analysis of knees synovial biopsies from SLE-associated arthritis showed an inverse correlation between SPARC and key autoimmune genes. These results point to SPARC down-regulation as a leading event characterizing SLE and rheumatoid arthritis pathogenesis.