RESUMO
Clusterin (Clu), an extracellular chaperone, exhibits characteristics of soluble innate immunity receptors, as assessed by its ability to bind some bacteria strains. In this study, we report that Clu also binds specifically to late apoptotic cells but not to live, early apoptotic, or necrotic cells. Histones, which accumulate on blebs during the apoptotic process, represent privileged Clu-binding motifs at the surface of late apoptotic cells. As a consequence, Clu potentiates, both in vitro and in vivo, the phagocytosis of late apoptotic cells by macrophages. Moreover, the increased phagocytosis of late apoptotic cells induced by Clu favors the presentation and cross-presentation of apoptotic cell-associated antigens. Finally, we observed that, in a model of apoptotic cell-induced autoimmunity, and relative to control mice, Clu(-/-) mice develop symptoms of autoimmunity, including the generation of anti-dsDNA antibodies, deposition of immunoglobulins and complement components within kidneys, and splenomegaly. These results identify Clu as a new molecule partner involved in apoptotic cell efferocytosis and suggest a protective role for Clu in inflammation and autoimmune diseases.
Assuntos
Apresentação de Antígeno/genética , Autoantígenos/imunologia , Doenças Autoimunes/imunologia , Clusterina/imunologia , Esplenomegalia/imunologia , Animais , Anticorpos Antinucleares/biossíntese , Apoptose/imunologia , Autoantígenos/genética , Doenças Autoimunes/genética , Doenças Autoimunes/patologia , Clusterina/genética , Técnicas de Cocultura , Apresentação Cruzada/genética , Células Dendríticas/citologia , Células Dendríticas/imunologia , Expressão Gênica , Humanos , Rim/imunologia , Rim/patologia , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/imunologia , Macrófagos/citologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fagocitose , Cultura Primária de Células , Baço/imunologia , Baço/patologia , Esplenomegalia/genética , Esplenomegalia/patologiaRESUMO
Neutrophils are short-lived innate immune cells that rapidly die by apoptosis. A rapid and efficient clearance of apoptotic cells is crucial to avoid autoimmunity. This process involves cell alterations, endocytic receptors expressed by phagocytic cells and soluble bridging molecules (opsonins) that facilitate internalization of apoptotic cells by phagocytes. Neutrophils constitutively express the prototypic long pentraxin PTX3 that binds to apoptotic cells and modulates their clearance. We thus evaluated whether endogenous PTX3 may interfere with the capture of apoptotic neutrophils. We observed that PTX3 accumulates in blebs at the surface of late apoptotic neutrophils, resulting from its active translocation from granules to the membrane. A neutralizing anti-PTX3 monoclonal Ab (mAb) inhibits the capture of late apoptotic neutrophils by macrophages. This study shows that intracellular PTX3 translocates at the surface of late apoptotic neutrophils and acts as an 'eat-me' molecule for their recognition and capture by macrophages.
