Interleukin-33 Protects Ischemic Brain Injury by Regulating Specific Microglial Activities

Luo, Qianping; Fan, Yong; Lin, Lili; Wei, Jingjing; Li, Zuanfang; Li, Yongkun; Nakae, Susumu; Lin, Wei; Chen, Qi

doi:10.1016/j.neuroscience.2018.05.047

Cited by 36 publications

(24 citation statements)

References 68 publications

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“…7) expressing both pro-inflammatory (M1) and alternatively activated (M2) genes simultaneously. This is consistent with studies showing that IL-33 acts directly on the resident microglia and contributes to their altered phenotype 58,139 , and that human glioma specimens contain macrophage with diverse states 140 . Independent it is clear by the data provided herein that the IL-33 environment educates TAMs to drive glioma progression and that the nuclear function of IL-33 is required.…”

Section: Discussionsupporting

confidence: 91%

Glioma-derived IL-33 orchestrates an inflammatory brain tumor microenvironment that accelerates glioma progression

et al. 2020

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Despite a deeper molecular understanding, human glioblastoma remains one of the most treatment refractory and fatal cancers. It is known that the presence of macrophages and microglia impact glioblastoma tumorigenesis and prevent durable response. Herein we identify the dual function cytokine IL-33 as an orchestrator of the glioblastoma microenvironment that contributes to tumorigenesis. We find that IL-33 expression in a large subset of human glioma specimens and murine models correlates with increased tumor-associated macrophages/monocytes/microglia. In addition, nuclear and secreted functions of IL-33 regulate chemokines that collectively recruit and activate circulating and resident innate immune cells creating a pro-tumorigenic environment. Conversely, loss of nuclear IL-33 cripples recruitment, dramatically suppresses glioma growth, and increases survival. Our data supports the paradigm that recruitment and activation of immune cells, when instructed appropriately, offer a therapeutic strategy that switches the focus from the cancer cell alone to one that includes the normal host environment.

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Section: Discussionsupporting

confidence: 91%

Glioma-derived IL-33 orchestrates an inflammatory brain tumor microenvironment that accelerates glioma progression

et al. 2020

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“…It is generally understood that mechanical, chemical, trauma injury and IRI to several organs, including kidney, liver, lung, and brain, lead to rapid release of IL-33, presumably by damaged cells, further supporting the role of IL-33 as an alarmin ( 7 , 18 , 29 , 31 , 47 , 51 , 52 ). However, except during brain trauma ( 47 ) and kidney IRI ( 7 ) (and section First Evidence of an iNKT Cell/IL-33 Biological Axis Mediating Inflammation During Renal IR: Relevance to Liver and Lung?…”

Section: Inkt Cells In the Initiation/propagation Of Sterile Inflammamentioning

confidence: 98%

“…Another element supporting the role of IL-33 in tissue repair is the targeting of Treg and ILC2, contributing to resolution of inflammation of the intestine ( 62 ), skeletal muscles ( 63 ) and skin/wound repair ( 64 ). Lastly, IL-33 counteracts pro-Th1 inflammatory responses by targeting the shift from M1 to M2 macrophages ( 51 , 65 , 66 ). Whether these protective IL-33-driven functions are influenced by iNKT cells is unknown because interactions between Treg and iNKT cells, or ILC2 and iNKT cells, have been described only under pharmacological intervention ( 67 , 68 ).…”

Section: The Hypothesis Of a Functional Axis Between Inkt Cells And Imentioning

confidence: 99%

The Impact of Invariant NKT Cells in Sterile Inflammation: The Possible Contribution of the Alarmin/Cytokine IL-33

et al. 2018

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Although the contribution of iNKT cells to induction of sterile inflammation is now well-established, the nature of the endogenous compounds released early after cellular stress or damage that drive their activation and recruitment remains poorly understood. More precisely, iNKT cells have not been described as being reactive to endogenous non-protein damage-associated molecular-pattern molecules (DAMPs). A second subset of DAMPs, called alarmins, are tissue-derived nuclear proteins, constitutively expressed at high levels in epithelial barrier tissues and endothelial barriers. These potent immunostimulants, immediately released after tissue damage, include the alarmin IL-33. This factor has aroused interest due to its singular action as an alarmin during infectious, allergic responses and acute tissue injury, and as a cytokine, contributing to the latter resolutive/repair phase of sterile inflammation. IL-33 targets iNKT cells, inducing their recruitment in an inflammatory state, and amplifying their regulatory and effector functions. In the present review, we introduce the new concept of a biological axis of iNKT cells and IL-33, involved in alerting and controlling the immune cells in experimental models of sterile inflammation. This review will focus on acute organ injury models, especially ischemia-reperfusion injury, in the kidneys, liver and lungs, where iNKT cells and IL-33 have been presumed to mediate and/or control the injury mechanisms, and their potential relevance in human pathophysiology.

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“…In the mouse model of ischemic stroke induced by middle cerebral artery occlusion (MCAO), IL-33 mRNA and protein expression are obviously upregulated in lesions, and mature oligodendrocytes and astrocytes are responsible for this upregulation (9,(60)(61)(62).…”

Section: Il-33 In Ischemic Strokementioning

confidence: 99%

Therapeutic Opportunities of Interleukin-33 in the Central Nervous System

et al. 2021

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Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is involved in various diseases. IL-33 exerts its effects via its heterodimeric receptor complex, which comprises suppression of tumorigenicity 2 (ST2) and the IL-1 receptor accessory protein (IL-1RAP). Increasing evidence has demonstrated that IL-33/ST2 signaling plays diverse but crucial roles in the homeostasis of the central nervous system (CNS) and the pathogenesis of CNS diseases, including neurodegenerative diseases, cerebrovascular diseases, infection, trauma, and ischemic stroke. In the current review, we focus on the functional roles and cellular signaling mechanisms of IL-33 in the CNS and evaluate the potential for diagnostic and therapeutic applications.

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Interleukin-33 Protects Ischemic Brain Injury by Regulating Specific Microglial Activities

Cited by 36 publications

References 68 publications

Glioma-derived IL-33 orchestrates an inflammatory brain tumor microenvironment that accelerates glioma progression

Glioma-derived IL-33 orchestrates an inflammatory brain tumor microenvironment that accelerates glioma progression

The Impact of Invariant NKT Cells in Sterile Inflammation: The Possible Contribution of the Alarmin/Cytokine IL-33

Therapeutic Opportunities of Interleukin-33 in the Central Nervous System

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