IL-33 receptor ST2 regulates the cognitive impairments associated with experimental cerebral malaria

PLoS Pathogens

Anthony Laugeray¹  Céline Montécot¹  Maëliss Sivoyon¹  Flora Reverchon¹  Sandra Meme¹  François Erard¹  Arnaud Menuet¹  Bernhard Ryffel²  Isabelle Maillet³  Valérie F. J. Quesniaux³  Jennifer Palomo³  William Meme³  Améziane Herzine³  Stéphane Mortaud³ 

[1] CNRS, UMR7355, Orleans, France;Division of Rheumatology, Departments of Internal Medicine Specialties and of Pathology-Immunology, University of Geneva School of Medicine, Geneva, Switzerland;Experimental and Molecular Immunology and Neurogenetics, University of Orleans, Orleans, France

关键词: Cerebral malaria;    Cognitive impairment;    Microglial cells;    Hippocampus;    Mouse models;    Cognitive neurology;    Central nervous system;    Astrocytes;   

DOI  :  10.1371/journal.ppat.1006322

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Cerebral malaria (CM) is associated with a high mortality rate and long-term neurocognitive impairment in survivors. The murine model of experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA (PbA)-infection reproduces several of these features. We reported recently increased levels of IL-33 protein in brain undergoing ECM and the involvement of IL-33/ST2 pathway in ECM development. Here we show that PbA-infection induced early short term and spatial memory defects, prior to blood brain barrier (BBB) disruption, in wild-type mice, while ST2-deficient mice did not develop cognitive defects. PbA-induced neuroinflammation was reduced in ST2-deficient mice with low Ifng, Tnfa, Il1b, Il6, CXCL9, CXCL10 and Cd8a expression, associated with an absence of neurogenesis defects in hippocampus. PbA-infection triggered a dramatic increase of IL-33 expression by oligodendrocytes, through ST2 pathway. In vitro, IL-33/ST2 pathway induced microglia expression of IL-1β which in turn stimulated IL-33 expression by oligodendrocytes. These results highlight the IL-33/ST2 pathway ability to orchestrate microglia and oligodendrocytes responses at an early stage of PbA-infection, with an amplification loop between IL-1β and IL-33, responsible for an exacerbated neuroinflammation context and associated neurological and cognitive defects.

【 授权许可】

CC BY