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 systemic lupus erythematosus (SLE). Sparc−/− mice developed earlier and more severe renal disease, multi-organ parenchymal damage, and arthritis than the wild-type 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 γδT cells. Gene profile analysis of knee 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.

Sangaletti S., Botti L., Gulino A., Lecis D., Bassani B., Portararo P., et al. (2021). SPARC regulation of PMN clearance protects from pristane-induced lupus and rheumatoid arthritis. ISCIENCE, 24(6) [10.1016/j.isci.2021.102510].

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

Cancila V.;Tripodo C.;
2021-05-01

Abstract

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 systemic lupus erythematosus (SLE). Sparc−/− mice developed earlier and more severe renal disease, multi-organ parenchymal damage, and arthritis than the wild-type 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 γδT cells. Gene profile analysis of knee 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.
mag-2021
Settore MED/08 - Anatomia Patologica
Settore MED/05 - Patologia Clinica
Sangaletti S., Botti L., Gulino A., Lecis D., Bassani B., Portararo P., et al. (2021). SPARC regulation of PMN clearance protects from pristane-induced lupus and rheumatoid arthritis. ISCIENCE, 24(6) [10.1016/j.isci.2021.102510].
File in questo prodotto:
File Dimensione Formato  
iScience Sparc regulation of PMN clearance protects from pristane-induced lupus and rheumatoid arthritis.pdf

accesso aperto

Tipologia: Versione Editoriale
Dimensione 5.99 MB
Formato Adobe PDF
5.99 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10447/532010
Citazioni
  • ???jsp.display-item.citation.pmc??? 2
  • Scopus 6
  • ???jsp.display-item.citation.isi??? 5
social impact