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

Author:

Sangaletti Sabina,Botti Laura,Gulino Alessandro,Lecis Daniele,Bassani Barbara,Portararo Paola,Milani Matteo,De Cecco Loris,Dugo Matteo,Tripodo ClaudioORCID,Colombo Mario P.

Abstract

AbstractOne step along the pathogenesis of Systemic lupus erythematosus (SLE) is associated with polymorphonuclear leukocyte (PMN) death and their ineffective removal by M2-macrophages. The secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein with unexpected immunosuppressive function in M2-macrophages and myeloid cells. To investigate the role of SPARC in autoimmunity, we adopted a pristane–induced model of lupus in mice, which recapitulates clinical manifestations of human SLE. Sparc-/- mice developed earlier and more severe renal disease, lung and liver parenchymal damage than the WT counterpart. Most prominently, Sparc-/- mice had anticipated and severe occurrence of arthritis. An intermediate phenotype was obtained in Sparc+/- hemizygous mice, a result that suggests Sparc gene-dosage as relevant in autoimmune-related events. Mechanistically, a defective Sparc expression in PMN blocks their clearance by macrophages, through a defective delivery of eat-me and don’t eat-me signals. Sparc-/- PMN that escape macrophage scavenging becomes a source of autoantigens for dendritic cell (DC) presentation and a direct stimulus for IL-17 expression in γδ-T-cells. Gene profile analysis of synovial biopsies of knees affected by SLE-associated arthritis showed an inverse correlation between SPARC and key autoimmune genes. These results point to SPARC down-regulation as a key event characterizing SLE and associated rheumatoid arthritis pathogenesis.

Publisher

Cold Spring Harbor Laboratory

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