Critical role of IL‐33 receptor ST2 in experimental cerebral malaria development

Abstract

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. Keywords:Experimental cerebral malaria r IL-33 r Plasmodium berghei ANKA r Sporozoite r ST2Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMalaria is the most common parasitosis in the world, leading to around 650 000 deaths in 2012, especially African children [1]. Plasmodium falciparum is responsible for the major and oftenCorrespondence: Dr. Valérie F. J. Quesniaux e-mail: quesniaux@cnrs-orleans.fr fatal cerebral malaria complication [2]. The pathophysiology of cerebral malaria, which remains poorly understood, is associated with microvessel obstruction and excessive inflammation in the brain. Indeed, studies in humans and mice have shown that cerebral malaria correlates with the sequestration of RBCs, * These authors contributed equally to this work. The contribution of the innate response in ECM development has remained more elusive. Indeed, although MyD88-deficient mice show protection against ECM upon PbA sporozoite infection ([11] and our unpublished data), little contribution of the TLRs pathways was reported [12,13]. MyD88 adaptor is also used by receptors of the IL-1 family, but both IL-1β and IL-18 seem dispensable for induction of ECM [11]. MyD88 is further shared by more recently characterized members of the IL-1 family such as IL-33 and IL-36. We were interested in studying the implication of IL-33, a modulator of T H 2 responses, in ECM development since the T H 1/T H 2 balance has been shown to modulate ECM [10,14]. IL-33, essential in innate and epithelial immune response [15,16], activates T H 2 T-cell differentiation and release of T H 2 cytokines and chemokines. IL-33 is overexpressed in clinical or experimental visceral leishmaniasis and it suppresses T H 1 responses in mice infected with Leishmania donovani [17]. IL-33 levels are increased in the plasma of infants with severe malaria, as compared with infection-free controls [18]. In addition, IL-33 has been associated with some cerebral diseases. IL-33 is implicated in Toxoplasma gondii induced encephalitis in mice, and was shown to attenuate EAE by suppressing IL-17 and IFN-γ production [19,20]. IL-33 is expressed within CNS by brain endothelial cells and astrocytes, LPS upregulating IL-33 expression by astrocytes [21]. In view of IL-33 implication in CNS pathologies and its role in modulating the T H 2/T H 1 balance, we investigated the role of IL-33 pathway in ECM development.Here, ECM development in response to PbA infection was investigated in mice deficient for IL-33 receptor, ST2. We show that br...

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

“…IL-33 is strongly expressed within the CNS [22], and we recently showed that the high steady-state levels of IL-33 protein found in naïve brain doubled during ECM, after blood stage or sporozoite Pb A-infection [11]. Since IL-33/ST2 has been implicated in Pb A-induced ECM, we first assessed the cellular source of IL-33 brain expression.…”

“…As in humans, increased levels of inflammatory cytokines and chemokines are present in the brain of Plasmodium berghei ANKA ( Pb A) infected mice during experimental cerebral malaria (ECM) [10, 11]. We showed recently that IL-33 protein levels are increased in the brain undergoing ECM, and that mice deficient for IL-33 receptor ST2 display resistance to ECM after Pb A sporozoite or blood stage infection with a reduced ICAM expression and microvascular obstruction in the brain, and with decreased pathogenic T cell sequestration and LT-α induction [11].…”

“…We showed recently that IL-33 protein levels are increased in the brain undergoing ECM, and that mice deficient for IL-33 receptor ST2 display resistance to ECM after Pb A sporozoite or blood stage infection with a reduced ICAM expression and microvascular obstruction in the brain, and with decreased pathogenic T cell sequestration and LT-α induction [11]. At steady state, part of the immune cells present in the brain, including some CD4 + and CD8 + T cells, NKT cells and granulocytes, express ST2 receptor.…”

“…At steady state, part of the immune cells present in the brain, including some CD4 + and CD8 + T cells, NKT cells and granulocytes, express ST2 receptor. But none of those ST2 + immune cells were clearly increased in the brain undergoing ECM [11], suggesting that IL-33/ST2 pathway from other cell types, such as in central nervous system (CNS) cells, may be involved.…”

Interleukin 33 Initiates CNS Inflammation Following Traumatic Injury

“…Studies exist regarding IL-33 in other CNS conditions, including stroke Luo et al, 2015), neuropathic pain (Zarpelon et al, 2016;Liu et al, 2015), infection (Peng et al, 2013;Hudson et al, 2008;Palomo et al, 2015;Tong and Lu, 2015), and age related macular degeneration (Xi et al, 2016), but given a dearth of literature these will not be specifically discussed here.…”