Nucleosomes inhibit phagocytosis of apoptotic thymocytes by peritoneal macrophages from MRL+/+ lupus-prone mice

The nucleosome, the basic structure of chromatin and normal product of cell apoptosis, plays a pivotal role both in the induction and the pathogenesis of systemic lupus erythematosus (SLE), Nucleosomes have been found to circ ulate at high levels in patients with SLE and apoptosis of lymphoid cells i s increased during human and murine lupus, In this study, we examined the p resence of possible defects iu clearance mechanisms of apoptotic cells in m urine lupus, and questioned further whether nucleosomes could compromise th is phagocytic process. There did not appear to be any intrinsic functional defect of macrophages from young MRL+/+ lupus-prone mice to recognize and p hagocytose apoptotic thymocytes, Nucleosomes, as a mimic of increased cell apoptotsis in vivo, induced a strong, dose-dependent, inhibition of phagocy tosis of apoptotic thymocytes by young, pre-autoimmune, macrophages of MRL/+ mice, whereas macrophages of non-autoimmune C3H mice only exhibited a tr end to inhibition. The nucleosome-elicited inhibitory effect persisted duri ng the development of the autoimmune response and appeared to be specific f or the molecular mechanisms involved in macrophage phagocytosis of apoptoti c cells. Our data suggest that nucleosome elicited inhibition of phagocytos is of apoptotic cells by MRL+/+ macrophages before the onset of the autoimm une response contribute, in a positive loop, to sustain and/or augment the levels of circulating (and potentially immunogenic) nucleosomes in lupus.