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

158

115

Deficiency of complement in humans and mice is associated with the development of lupus and with abnormal repair of inflammatory and immune complex-mediated tissue injury. Here we ask whether similar defects in the resolution of inflammation are found in mice prone to spontaneous lupus. We compared the response to an i.p. injection of thioglycolate between two lupus-prone strains (MRL/Mp and NZB/W) and two non lupus-prone strains of mice (C57BL/6 and BALB/c). In all four strains the influx of polymorphonuclear neutrophils (PMN) was similar. However, by 96 h clearance of PMN in the control strains was complete, whereas in the autoimmune-prone strains PMN were still detectable. The number of mononuclear cells recruited was markedly reduced in the lupus-prone strains compared with the controls, and their phenotype was different. The lupus-prone strains had significantly fewer elicited macrophages that were CD11b-high and Ly6C-negative. In lupus-prone mice at 24 h there was a significantly increased number of apoptotic PMN free in the peritoneum, accompanied by a reduced percentage of macrophages containing apoptotic bodies, suggesting a defect in their uptake. An impaired ability of resident peritoneal macrophages from lupus-prone mice to engulf apoptotic cells was demonstrated by in vivo and in vitro cell clearance assays. These observations indicate that lupus-prone strains have an abnormal inflammatory response to thioglycolate and an intrinsic impairment in apoptotic cell uptake. These findings have implications for the initiation of autoimmunity, as lupus autoantigens are expressed on dying cells, and impaired disposal of these could enhance the development of autoimmunity.

Section: Discussioncontrasting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Lupus-Prone Mice Have an Abnormal Response to Thioglycolate and an Impaired Clearance of Apoptotic Cells

Potter

Cortés-Hernández

Quartier

et al. 2003

158

115

“…Additional evidence for the role of nucleosomes in the recognition and clearance of apoptotic cells comes from the observation that an excess of nucleosomes partially inhibits clearance of apoptotic cells by macrophage (52). The simplest interpretation of this experimental result is that nucleosomes interact with receptors that mediate clearance.…”

Section: Discussionmentioning

confidence: 99%

Nucleosomes Are Exposed at the Cell Surface in Apoptosis

Radic

Marion

Monestier

2004

199

184

Apoptotic cells are considered the source of DNA, histones, and nucleoprotein complexes that drive the production of autoantibodies in systemic lupus erythematosus. However, the role of apoptotic cells in the activation of the immune system is not clear. To explore interactions that may initiate or sustain the production of anti-nuclear autoantibodies, we characterized the binding of a large panel of monoclonal autoantibodies to apoptotic cells. Autoantibodies to DNA, individual core histones, histone-DNA complexes, or the native nucleosome core particle revealed a consistent and specific binding pattern in confocal microscopy. Immunoreactive epitopes were detected in the cytoplasm and accumulated along the surface of the fragmenting nucleus in a caspase-dependent manner. Ag-Ab complexes on nuclear fragments that had emerged from the plasma membrane were accessible to anti-isotype-reactive microparticles. Moreover, autoantibodies specific for the nucleosome core or its molecular components selectively precipitated a complex of core histones and DNA from the cytosol at 4 h after induction of apoptosis. These observations identify distinct steps in the release of nucleosomes from the nucleus and their exposure at the cell surface. Furthermore, the results indicate a direct role for nucleosomes in the execution of apoptosis, clearance of apoptotic cells, and regulation of anti-nuclear autoantibody production.

“…Many investigators have reported that impaired clearance of dying cells plays a pathogenic role in the development of autoimmunity (57)(58)(59)(60). Moreover, it has been reported that macrophages of autoimmune-prone mice, such as MRL/Mp or NOD mice, showed reduced phagocytosis of apoptotic cells (61)(62)(63)(64)(65). To prevent apoptotic cells from triggering autoimmunity, there are various firewall systems in our body.…”

Section: Discussionmentioning

confidence: 99%

Neutrophils Accelerate Macrophage-Mediated Digestion of Apoptotic Cells In Vivo as Well as In Vitro

Iyoda

Nagata

Akashi³

et al. 2005

It is generally believed that the clearance of apoptotic cells does not lead to inflammation. In contrast, we previously found that injection of apoptotic cells into the peritoneal cavity induced the expression of an inflammatory chemokine, MIP-2, and infiltration of neutrophils, and that anti-MIP-2 Abs suppressed the infiltration significantly. Because our previous study showed that whole-body x-irradiation caused neutrophil infiltration into the thymus along with T cell apoptosis, we examined the role of neutrophils in apoptotic cell clearance. Neutrophil infiltration reached a peak 12 h after irradiation with 1 Gy of x-rays. Immunohistological analysis revealed that apoptotic cells disappeared dramatically from 10.5 to 12 h after x-irradiation. As neutrophils moved from an inner area of the cortex to the periphery, apoptotic cells disappeared concomitantly. Either anti-MIP-2 or anti-CXCR2 Abs suppressed neutrophil infiltration significantly, and the suppression of neutrophil infiltration by anti-MIP-2 Abs delayed the disappearance of apoptotic cells. Moreover, macrophage-mediated digestion of apoptotic thymocytes was accelerated in vitro on coculturing with neutrophils, even if neutrophils were separated from macrophages. These results suggest that neutrophils are recruited to the thymus mainly by MIP-2 after whole-body x-irradiation and that such neutrophils may not induce inflammation but rather accelerate complete digestion of apoptotic cells by macrophages.