Brain endothelial cells exposure to malaria parasites links type I interferon signalling to antigen presentation, immunoproteasome activation, endothelium disruption, and cellular metabolism
Cerebral malaria (CM) lethality is attributable to induction of brain edema induction but the cellular mechanisms involving brain microvascular endothelium in CM pathogenesis are unexplored. Activation of the STING-INFb-CXCL10 axis in brain endothelial cells (BECs) is a prominent component of the in...
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Published in | Frontiers in immunology Vol. 14; p. 1149107 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
Switzerland
Frontiers Media S.A
2023
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Subjects | |
Online Access | Get full text |
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Summary: | Cerebral malaria (CM) lethality is attributable to induction of brain edema induction but the cellular mechanisms involving brain microvascular endothelium in CM pathogenesis are unexplored.
Activation of the STING-INFb-CXCL10 axis in brain endothelial cells (BECs) is a prominent component of the innate immune response in CM development in mouse models. Using a T cell-reporter system, we show that Type 1 IFN signaling in BECs exposed to
-infected erythrocytes (
-IE), functionally enhances MHC Class-I antigen presentation through gamma-interferon independent immunoproteasome activation and impacted the proteome functionally related to vesicle trafficking, protein processing/folding and antigen presentation.
assays showed that Type 1 IFN signaling and immunoproteasome activation are also involved in the dysfunction of the endothelial barrier through disturbing gene expression in the Wnt/
-catenin signaling pathway. We demonstrate that IE exposure induces a substantial increase in BECs glucose uptake while glycolysis blockade abrogates INFb secretion impairing immunoproteasome activation, antigen presentation and Wnt/
-catenin signaling.
Metabolome analysis show that energy demand and production are markedly increased in BECs exposed to IE as revealed by enriched content in glucose and amino acid catabolites. In accordance, glycolysis blockade
delayed the clinical onset of CM in mice. Together the results show that increase in glucose uptake upon IE exposure licenses Type 1 IFN signaling and subsequent immunoproteasome activation contributing to enhanced antigen presentation and impairment of endothelial barrier function. This work raises the hypothesis that Type 1 IFN signaling-immunoproteasome induction in BECs contributes to CM pathology and fatality (1) by increasing antigen presentation to cytotoxic CD8+ T cells and (2) by promoting endothelial barrier dysfunction, that likely favor brain vasogenic edema. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Reviewed by: Alister Craig, Liverpool School of Tropical Medicine, United Kingdom; Agam Prasad Singh, National Institute of Immunology (NII), India This article was submitted to Parasite Immunology, a section of the journal Frontiers in Immunology Edited by: Reginaldo G. Bastos, Washington State University, United States |
ISSN: | 1664-3224 1664-3224 |
DOI: | 10.3389/fimmu.2023.1149107 |