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bioRxiv · 10.1101/2020.08.10.243816

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

Sangaletti, S.·Botti, L.·Gulino, A.·Lecis, D.·Bassani, B.·Portararo, P.·Milani, M.·De Cecco, L.·Dugo, M.·Tripodo, C.·Colombo, M. P.
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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-/- 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 dont 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 {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.

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Sangaletti, S., Botti, L., Gulino, A., Lecis, D., Bassani, B., Portararo, P., Milani, M., De Cecco, L., Dugo, M., Tripodo, C., Colombo, M. P.. 2020-08-10. SPARC regulation of PMN clearance protects from pristane induced lupus and rheumatoid arthritis. https://doi.org/10.1101/2020.08.10.243816

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