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

Abstract

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.

Spinal IL‐33/ST2 signaling mediates chronic itch in mice through the astrocytic JAK2‐STAT3 cascade

“…In this study, spinal IL‐33 was found to be predominantly distributed in oligodendrocytes and astrocytes in the spinal cord of ACD mice, which is consistent with recent reports using IL‐33/citrine reporter mice (Reverchon et al, ). However, the cellular localization of ST2 in the central nervous system remains unclear.…”

Unravelling the roles of innate lymphoid cells in cerebral malaria pathogenesis

“…However, beside its effects as a pro‐Th2 inducer, IL‐33 could play a role as an early CNS endogenous mediator, acting through its intracellular molecular form, aspects that a systemic administration of exogenous IL‐33 will not reproduce. The IL‐33/ST2 pathway seems to play a role, not only on the development of cerebral malaria, but also on the associated cognitive defects as reported . Beside the pathogenic immune response involving cytokine and chemokine release leading to effector granzyme + CD8 + T cells, there seems to be another early inflammatory component within the CNS, taking place before the blood brain barrier (BBB) leakage.…”

“…The IL-33/ST2 pathway seems to play a role, not only on the development of cerebral malaria, 8 but also on the associated cognitive defects as reported. 12 Beside the pathogenic immune response involving cytokine and chemokine release leading to effector granzyme + CD8 + T cells, there seems to be another early inflammatory component within the CNS, taking place before the blood brain barrier (BBB) leakage.…”

Malaria, enfermedad tropical de múltiples métodos diagnósticos

“…La fisiopatología es la cito-adherencia al endotelio cerebral de los glóbulos rojos, plaquetas y leucocitos infectados, que conducen a la obstrucción de los microvasos y la inflamación excesiva del cerebro [20,21]. Se puede presentar de forma súbita o gradual después de una crisis convulsiva desencadenante.…”