Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.10.243816v1?rss=1 Authors: Sangaletti, S., Botti, L., Gulino, A., Lecis, D., Bassani, B., Portararo, P., Milani, M., De Cecco, L., Dugo, M., Tripodo, C., Colombo, M. P. Abstract: One 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 deficient mice developed earlier and more severe renal disease, lung and liver parenchymal damage than the WT counterpart. Most prominently, Sparc deficient 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 deficient PMN that escape macrophage scavenging becomes a source of autoantigens for dendritic cell (DC) presentation and a direct stimulus for IL17 expression in gamma delta 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. Copy rights belong to original authors. Visit the link for more info