| Autor: |
Leleu I; Center for Infection and Immunity of Lille-CIIL, Institut Pasteur De Lille, Univ. Lille, Lille, France., Genete D; Center for Infection and Immunity of Lille-CIIL, Institut Pasteur De Lille, Univ. Lille, Lille, France., Desnoulez SS; Institut Pasteur De Lille, Univ. Lille, Cnrs, Inserm, Chu Lille, Lille, France., Saidi N; Center for Infection and Immunity of Lille-CIIL, Institut Pasteur De Lille, Univ. Lille, Lille, France., Brodin P; Center for Infection and Immunity of Lille-CIIL, Institut Pasteur De Lille, Univ. Lille, Lille, France., Lafont F; Center for Infection and Immunity of Lille-CIIL, Institut Pasteur De Lille, Univ. Lille, Lille, France.; Institut Pasteur De Lille, Univ. Lille, Cnrs, Inserm, Chu Lille, Lille, France., Tomavo S; Institute for Integrative Biology of the Cell (I2BC), Université Paris-Saclay, Gif-sur-Yvette, France., Pied S; Center for Infection and Immunity of Lille-CIIL, Institut Pasteur De Lille, Univ. Lille, Lille, France. |
| Abstrakt: |
Cerebral malaria is a neuroinflammatory disease induced by P. falciparum infection. In animal models, the neuro-pathophysiology of cerebral malaria results from the sequestration of infected red blood cells (iRBCs) in microvessels that promotes the activation of glial cells in the brain. This activation provokes an exacerbated inflammatory response characterized by the secretion of proinflammatory cytokines and chemokines, leading to brain infiltration by pathogenic CD8 + T lymphocytes. Astrocytes are a major subtype of brain glial cells that play an important role in maintaining the homeostasis of the central nervous system, the integrity of the brain-blood barrier and in mounting local innate immune responses. We have previously shown that parasitic microvesicles ( Pb A-MVs) are transferred from iRBCs to astrocytes. The present study shows that an unconventional LC3-mediated autophagy pathway independent of ULK1 is involved in the transfer and degradation of Pb A-MVs inside the astrocytes. We further demonstrate that inhibition of the autophagy process by treatment with 3-methyladenine blocks the transfer of Pb A-MVs, which remain localized in the astrocytic cell membrane and are not internalized. Moreover, bafilomycin A 1 , another drug against autophagy promotes the accumulation of Pb A-MVs inside the astrocytes by inhibiting the fusion with lysosomes, and prevents ECM in mice infected with Pb A. Finally, we establish that RUBCN/rubicon or ATG5 silencing impede astrocyte production in CCL2 and CXCL10 chemokines induced by Pb A stimulation. Altogether, our data suggest that a non-canonical autophagy-lysosomal pathway may play a key role in cerebral malaria through regulation of brain neuro-inflammation by astrocytes. |
