Interleukin-1 mediates ischaemic brain injury via distinct actions on endothelial cells and cholinergic neurons

Wong, Raymond; Lénárt, Nikolett; Hill, L. R.; Toms, Lauren; Coutts, Graham; Martinecz, Bernadett; Császár, Eszter; Nyíri, Gábor; Papaemmanouil, Athina; Waisman, Ari; Müller, Werner; Schwaninger, Markus; Rothwell, Nancy J.; Francis, Sheila; Pinteaux, Emmanuel; Dénes, Ádám; Allan, Stuart M.

doi:10.1016/j.bbi.2018.11.012

Cited by 50 publications

(48 citation statements)

References 86 publications

(105 reference statements)

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“…51 It is well documented that activated microglia secrete an array of pro-inflammatory cytokines including TNF-α and IL-1β, and both are involved in disruption of BBB. [52][53][54][55] However, the lack of other cytokines (ie, TNF-a) being investigated in the present study is a limitation and an area for future research. Of course, our study did not prove the upstream mechanism by which HS inhibits NLRP3 inflammasome activation in ischemic stroke.…”

Section: F I G U R Ementioning

confidence: 95%

Hypertonic saline mediates the NLRP3/IL‐1β signaling axis in microglia to alleviate ischemic blood‐brain barrier permeability by downregulating astrocyte‐derived VEGF in rats

et al. 2020

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Introduction The aim of this study was to explore whether the antibrain edema of hypertonic saline (HS) is associated with alleviating ischemic blood‐brain barrier (BBB) permeability by downregulating astrocyte‐derived vascular endothelial growth factor (VEGF), which is mediated by microglia‐derived NOD‐like receptor protein 3 (NLRP3) inflammasome. Methods The infarct volume and BBB permeability were detected. The protein expression level of VEGF in astrocytes in a transient focal brain ischemia model of rats was evaluated after 10% HS treatment. Changes in the NLRP3 inflammasome, IL‐1β protein expression, and the interleukin‐1 receptor (IL1R1)/pNF‐кBp65/VEGF signaling pathway were determined in astrocytes. Results HS alleviated the BBB permeability, reduced the infarct volume, and downregulated the expression of VEGF in astrocytes. HS downregulates IL‐1β expression by inhibiting the activation of the NLRP3 inflammasome in microglia and then downregulates VEGF expression by inhibiting the phosphorylation of NF‐кBp65 mediated by IL‐1β in astrocytes. Conclusions HS alleviated the BBB permeability, reduced the infarct volume, and downregulated the expression of VEGF in astrocytes. HS downregulated IL‐1β expression via inhibiting the activation of the NLRP3 inflammasome in microglia and then downregulated VEGF expression through inhibiting the phosphorylation of NF‐кBp65 mediated by IL‐1β in astrocytes.

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Section: F I G U R Ementioning

confidence: 95%

Hypertonic saline mediates the NLRP3/IL‐1β signaling axis in microglia to alleviate ischemic blood‐brain barrier permeability by downregulating astrocyte‐derived VEGF in rats

et al. 2020

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“…A randomized, double-blind, placebo-controlled trial of Anakinra was carried out in patients with acute stroke. Anakinra-treated patients showed lower systemic inflammation (white blood cells, neutrophil counts, C-reactive protein [CRP], and IL-6 levels) and cognitive impairment than placebo-treated patients (Dinarello, 2011;Wong et al, 2019). In addition, Anakinra was used to treat autoinflammation-associated epilepsy syndrome (DeSena et al, 2018).…”

Section: Il-1 Family Members In the Pathophysiology Of The Central Nementioning

confidence: 99%

Interleukin-1 and Related Cytokines in the Regulation of Inflammation and Immunity

et al. 2019

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Forty years after its naming, interleukin-1 (IL-1) is experiencing a renaissance brought on by the growing understanding of its context-dependent roles and advances in the clinic. Recent studies have identified important roles for members of the IL-1 family-IL-18, IL-33, IL-36, IL-37, and IL-38-in inflammation and immunity. Here, we review the complex functions of IL-1 family members in the orchestration of innate and adaptive immune responses and their diversity and plasticity. We discuss the varied roles of IL-1 family members in immune homeostasis and their contribution to pathologies, including autoimmunity and autoinflammation, dysmetabolism, cardiovascular disorders, and cancer. The trans-disease therapeutic activity of anti-IL-1 strategies argues for immunity and inflammation as a metanarrative of modern medicine. 2018). This suggests the evolutive relevance of balanced responses in the IL-1 system. Interleukin-1 receptor family members (ILRs) are present in all vertebrates and originated through ancestral gene duplication 25 S IN CE 1 99 4 T W T EN

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“…We posit here that further work in the preclinical and clinical arenas is warranted, as each will provide crucial information required to further the potential use of pharmacotherapies targeting IL-1-mediated signaling. We also believe that recently developed molecular tools aimed at delineating the roles of IL-1 signaling, such as IL-1R1 loxP/loxP mice and IL-1R1 Restore mice, will prove useful for determining the specific cell types and timelines critical for targeting IL-1 signaling post-TBI, similar to efforts in preclinical models for ischemia (Liu et al, 2015;Robson et al, 2016;Wong et al, 2019). Although IL-1-targeted therapies have been shown to be safe in clinical populations post-injury, the temporal requirements for targeting IL-1 signaling are important, and the optimization of timing post-injury should be analyzed thoroughly for studies moving forward.…”

Section: Discussionmentioning

confidence: 99%

“…In mice expressing IL-1R1 only in endothelial cells, mRNA expression of microglial cytokines, including IL-1β, is increased compared to WT controls (Liu et al, 2019). In a mouse model of cerebral ischemia, pan-neuronal, and brain endothelialspecific IL-1R1 deletion showed reduced infarct volume, with endothelial elimination attenuating BBB permeability and improving neurological function (Wong et al, 2019). Elimination of IL-1R1 in cholinergic neurons also improved functional outcomes and reduced infarct size, providing evidence that specific neuronal populations may be required for IL-1R1mediated effects within the CNS (Wong et al, 2019).…”

Section: Genetic Ko Modelsmentioning

confidence: 95%

“…In a mouse model of cerebral ischemia, pan-neuronal, and brain endothelialspecific IL-1R1 deletion showed reduced infarct volume, with endothelial elimination attenuating BBB permeability and improving neurological function (Wong et al, 2019). Elimination of IL-1R1 in cholinergic neurons also improved functional outcomes and reduced infarct size, providing evidence that specific neuronal populations may be required for IL-1R1mediated effects within the CNS (Wong et al, 2019). Another notable feature of IL-1-mediated signaling is the ability to drive sickness behaviors.…”

Section: Genetic Ko Modelsmentioning

confidence: 97%

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Contributions of Interleukin-1 Receptor Signaling in Traumatic Brain Injury

Thome

Reeder

Collins

et al. 2020

Front. Behav. Neurosci.

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Traumatic brain injury (TBI) in various forms affects millions in the United States annually. There are currently no FDA-approved therapies for acute injury or the chronic comorbidities associated with TBI. Acute phases of TBI are characterized by profound neuroinflammation, a process that stimulates the generation and release of proinflammatory cytokines including interleukin-1α (IL-1α) and IL-1β. Both forms of IL-1 initiate signaling by binding with IL-1 receptor type 1 (IL-1R1), a receptor with a natural, endogenous antagonist dubbed IL-1 receptor antagonist (IL-1Ra). The recombinant form of IL-1Ra has gained FDA approval for inflammatory conditions such as rheumatoid arthritis, prompting interest in repurposing these pharmacotherapies for other inflammatory diseases/injury states including TBI. This review summarizes the currently available preclinical and clinical literature regarding the therapeutic potential of inhibiting IL-1-mediated signaling in the context of TBI. Additionally, we propose specific research areas that would provide a greater understanding of the role of IL-1 signaling in TBI and how these data may be beneficial for the development of IL-1-targeted therapies, ushering in the first FDA-approved pharmacotherapy for acute TBI.

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Interleukin-1 mediates ischaemic brain injury via distinct actions on endothelial cells and cholinergic neurons

Cited by 50 publications

References 86 publications

Hypertonic saline mediates the NLRP3/IL‐1β signaling axis in microglia to alleviate ischemic blood‐brain barrier permeability by downregulating astrocyte‐derived VEGF in rats

Hypertonic saline mediates the NLRP3/IL‐1β signaling axis in microglia to alleviate ischemic blood‐brain barrier permeability by downregulating astrocyte‐derived VEGF in rats

Interleukin-1 and Related Cytokines in the Regulation of Inflammation and Immunity

Contributions of Interleukin-1 Receptor Signaling in Traumatic Brain Injury

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