Critical role of IL‐33 receptor ST2 in experimental cerebral malaria development |
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| Authors: | Jennifer Palomo Flora Reverchon Julie Piotet Anne‐Gaelle Besnard Aurélie Couturier‐Maillard Isabelle Maillet Maurel Tefit François Erard Dominique Mazier Bernhard Ryffel Valérie F. J. Quesniaux |
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| Affiliation: | 1. CNRS, UMR7355, Orleans, France;2. Experimental and Molecular Immunology and Neurogenetics, University of Orleans, Orleans, France;3. CIMI‐Paris (UPMC UMRS CR7, Inserm U1135, CNRS ERL 8255), Paris, France;4. Groupe Hospitalier Pitié‐Salpêtrière Service Parasitologie‐Mycologie, Paris, France |
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| Abstract: | Cerebral malaria, a severe complication of Plasmodium falciparum infection, can be modeled in murine Plasmodium berghei ANKA (PbA) infection. PbA‐induced experimental cerebral malaria (ECM) is CD8+ T‐cell mediated, and influenced by TH1/TH2 balance. Here, we show that IL‐33 expression is increased in brain undergoing ECM and we address the role of the IL‐33/ST2 pathway in ECM development. ST2‐deficient mice were resistant to PbA‐induced neuropathology. They survived >20 days with no ECM neurological sign and a preserved cerebral microcirculation, while WT mice succumbed within 10 days with ECM, brain vascular leakage, distinct microvascular pathology obstruction, and hemorrhages. Parasitemia and brain parasite load were similar in ST2‐deficient and WT mice. Protection was accompanied by reduced brain sequestration of activated CD4+ T cells and perforin+ CD8+ T cells. While IFN‐γ and T‐cell‐attracting chemokines CXCL9 and CXCL10 were not affected in the absence of functional ST2 pathway, the local expression of ICAM‐1, CXCR3, and LT‐α, crucial for ECM development, was strongly reduced, and this may explain the diminished pathogenic T‐cell recruitment and resistance to ECM. Therefore, IL‐33 is induced in PbA sporozoite infection, and the pathogenic T‐cell responses with local microvascular pathology are dependent on IL‐33/ST2 signaling, identifying IL‐33 as a new actor in ECM development. |
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| Keywords: | Experimental cerebral malaria IL‐33 Plasmodium berghei ANKA Sporozoite ST2 |
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