IgG opsonized nuclear remnants from dead cells cause systemic inflammation in SLE

Abstract

Deficiencies in the recognition and engulfment of apoptotic cells have been reported in patients with systemic lupus erythematosus (SLE). If dying cells are not promptly cleared, they undergo secondary necrosis and release nuclear autoantigens. Secondarily necrotic cell-derived material (SNEC) can be generated in vitro employing various methods. SNEC generated by either methods shows similar DNA content, light scatter characteristics, and binding pattern of dead and dying cell ligands and is readily recognized by autoantibodies (AAb) of many patients with SLE. In whole blood, AAb opsonize SNEC and foster its uptake by blood-borne non-professional phagocytes. We observed a significant secretion of the inflammatory cytokines IL-8 and TNF-α by phagocytes which had engulfed different types of opsonized SNEC. Phagocytosis of SNEC and the subsequent production of inflammatory cytokines were strongly influenced by the presence of DNA in this prey, since DNase I treatment reduced both the uptake of SNEC and the induction of IL-8 and TNF-α production. In conclusion, the proinflammatory phagocytosis by circulating phagocytes of IgG-opsonized cellular remnants fosters systemic inflammation in SLE.

Keywords::

• SNEC
• SLE
• inflammation
• cytokines
• phagocytosis

Declaration of interest: This work was supported by “Deutsche Forschungsgemeinschaft” SFB 643 (project B5) of the University Hospital of the University of Erlangen–Nuremberg, by the Programme Alban, the European Union Program of High Level Scholarships for Latin America, scholarship numbers “E04D047956VE” to L. E. M. and “E07D400430VE” to R. A. C and by the K. & R. Wucherpfennigstiftung. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.