Immunomodulation by interleukin-33 is protective in stroke through modulation of inflammation

Korhonen, Paula; Kanninen, Katja M.; Lehtonen, Šárka; Lemarchant, Sighild; Puttonen, Katja A.; Oksanen, Markku; Dhungana, Hiramani; Loppi, Sanna; Pollari, Eveliina; Wojciechowski, Sara; Kidin, Iurii; García‐Berrocoso, Teresa; Giralt, Dolors; Montaner, Joan; Koistinaho, Jari; Malm, Tarja

doi:10.1016/j.bbi.2015.06.013

Cited by 111 publications

(120 citation statements)

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“…IL-33 administration in AIS also resulted in changes in concentrations of IL-4 post-stroke. Korhonen et al showed that decreases in lesion size with post-stroke IL-33 administration was associated with increases in IL-4 levels in the penumbra post-AIS and that these improvements diminished with the administration of anti-IL-4 antibody [186]. These observations demonstrate the interaction of IL-4 in the neuroprotective cascade induced by IL-33 [186].…”

Section: Anti-inlammatory Il-33 In Aismentioning

confidence: 64%

“…Clinically, Korhonen et al demonstrated that the soluble ST2 receptor, a decoy receptor that inhibits the actions of IL-33, was higher in the plasma of patients with poorer outcomes as measured by the modiied Rankin score at 3 months post-AIS, while lower levels of this IL-33 inhibiting receptor were associated with beter outcomes [186]. In agreement with these indings, serum IL-33 levels have also been found to be signiicantly higher in patients with AIS compared with healthy controls, with higher levels of IL-33 associated with smaller infarct volumes amongst those in the AIS group [190].…”

Section: Anti-inlammatory Il-33 In Aismentioning

confidence: 99%

“…Administration of IL-33 in in-vivo and in-vitro models of AIS is associated with improved neurologic scores, smaller infarct volumes, as well as improvements in the level of cerebral edema and neuronal survival with a shift towards protective microglia phenotypes [174,186,187]. IL-33's protective efects, mediated via its ST2 transmembrane receptor, are thought to be partially mediated by IL-10, as IL-33 is known to induce IL-10 production by microglia and IL-10 knockout mice did not experience the protective, infarct shrinking efects of IL-33 administration post-AIS [174].…”

Section: Anti-inlammatory Il-33 In Aismentioning

confidence: 99%

“…IL-33 undergoes activating cleavage by caspase-1 and interacts with a host of immune cells to shift the neuroinlammatory response towards neuroprotective, anti-inlammatory microglial and Th2 cell phenotypes, increasing the release of anti-inlammatory cytokines IL-4, IL-5, and IL-10, while decreasing the release of pro-inlammatory cytokines like TNF-α [186,187]. IL-33 binds to suppression of tumorigenicity 2 (ST2) receptor, a receptor that can either be expressed on the membranes of astrocytes and microglia to increase microglia phagocytosis or as a soluble receptor [188].…”

Section: Anti-inlammatory Cytokine Interleukin-33mentioning

confidence: 99%

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Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke

Dugue¹,

Nath²,

Dugue³

et al. 2017

Mechanisms of Neuroinflammation

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This chapter will introduce the reader to the pathophysiology of two devastating neurologic events, traumatic brain injury (TBI) and acute ischemic stroke (AIS). Here we focus on the role of key pro-inlammatory and anti-inlammatory cytokines. Several experimental interventions have been found to modulate cytokine production and brain injury after AIS or TBI. Here minocycline, biological response modiiers, hormonal therapies, omega-3 faty acids, N-acetylcysteine, and cannabinoids will be discussed. In addition, the role of cytokine-induced inlammasomes in both TBI and AIS will be addressed and followed by discussion of pro-inlammatory cytokines (e.g., TNF-α, IL-1β, IL-18, and IFN-γ). Finally, the main anti-inlammatory cytokines, IL-33, IL-10, IL-6, and IL-4, will be discussed in the context of both TBI and AIS. It should be noted that the role of these cytokines is diverse and the dichotomization of classically pro-versus anti-inlammatory cytokines is being re-examined, as many of these cytokines have been found to play dual roles in TBI and AIS brain injury.Keywords: traumatic brain injury, ischemic stroke, cytokines, interleukins, inlammasome Pathophysiology of traumatic brain injuryTraumatic brain injury (TBI) is a major cause of death and disability worldwide [1,2]. It is one of the most commonly diagnosed neurological disorders in the United States, impacting people of a variety of ages and segments of society [3]. In Europe, the economic cost of © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.TBI is over 33 billion euros per year [4]. Continued surveillance and research is being done to reduce primary and secondary TBI [as well as acute ischemic stroke(AIS)]-induced brain injury [1].The pathophysiology of TBI begins with the initial brain trauma (i.e., the primary injury). This primary injury results from mechanical damage that disrupts the blood-brain barrier (BBB), alters the vasculature and damages brain tissue. The resulting injured glia and neurons release their intracellular contents (i.e., damage-associated molecular paterns; (DAMPs)) into the extracellular space and activate neighboring glia and neurons. Activated glia and neurons then produce molecular signals that can both exacerbate and mend the acute injury and contribute to long-term recovery [5][6][7][8][9]. These downstream molecular and cellular processes (i.e., the secondary injury in TBI) are the focus of many pre-clinical and clinical therapeutic studies. Secondary injury in TBI involves a host of molecular and cellular responses to the The pathophysiology of AIS and TBI share common mechanisms. The initial insult in AIS, an occlusion of blood low resulting in a core infarct zone surrounded by a poorly perfused penumbra, versus the initial primary physical impact in TBI both result in pe...

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Section: Anti-inlammatory Il-33 In Aismentioning

confidence: 64%

Section: Anti-inlammatory Il-33 In Aismentioning

confidence: 99%

Section: Anti-inlammatory Il-33 In Aismentioning

confidence: 99%

Section: Anti-inlammatory Cytokine Interleukin-33mentioning

confidence: 99%

See 2 more Smart Citations

Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke

Dugue¹,

Nath²,

Dugue³

et al. 2017

Mechanisms of Neuroinflammation

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show abstract

“…In the setting of experimental ischaemic stroke, exogenous IL-33 is protective; it reduces brain inflammation and the development of lesions [62][63][64]. In spinal cord injury models, IL-33 mediates neuronal protection via type 2 immune responses [65,66].…”

Section: Central Nervous Systemmentioning

confidence: 99%

Therapeutic Strategies for Targeting IL-33/ST2 Signalling for the Treatment of Inflammatory Diseases

Chen

Tsai

Yang

et al. 2018

Cell Physiol Biochem

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Interleukin (IL)-33, a member of the IL-1 family of cytokines, is involved in innate and adaptive immune responses via interaction with its receptor, ST2. Activation of ST2 signalling by IL-33 triggers pleiotropic immune functions in multiple ST2-expressing immune cells, including macrophages, neutrophils, eosinophils, basophils, mast cells, type 2 helper T cells, regulatory T cells, and group 2 innate lymphoid cells. IL-33-mediated effector functions contribute to the tissue inflammatory and reparative responses in various organs including lung, skin, kidney, central nerve system, cardiovascular system, and gastrointestinal system. Endogenous IL-33/ ST2 signaling exhibits diverse immune regulatory functions during progression of different diseases. IL-33 likely functions as a disease sensitizer and plays pathological roles in inflamed tissues in allergic disorders that involve hyperreactive immune responses in the context of skin and pulmonary allergy. However, IL-33 also mediates tissue-protective functions during the recovery phase following tissue injury in the central nerve system and gastrointestinal system. Modulation of the IL-33/ST2 axis, therefore, represents a promising strategy for treating immune disorders that involve dysregulation of the cytokine signalling. In the past two decades, therapeutic strategies blocking IL-33/ST2 have been extensively studied for the treatment of diseases in animal models. In this review, the current progress on the development of therapeutic biologics for targeting IL-33/ST2 signalling in inflammatory diseases is summarized.

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Soluble ST2 predicts outcome and hemorrhagic transformation after acute stroke

Wolcott

Batra

Bevers

et al. 2017

Ann Clin Transl Neurol

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Objective ST2 is a member of the toll‐like receptor superfamily that can alter inflammatory signaling of helper T‐cells. We investigated whether soluble ST2 (sST2) could independently predict outcome and hemorrhagic transformation (HT) in the setting of stroke.MethodsWe measured sST2 in patients enrolled in the Specialized Program of Translational Research in Acute Stroke (SPOTRIAS) network biomarker study. 646 patients had plasma samples collected at the time of hospital admission and 210 patients had a second sample collected 48 h after stroke onset. Functional outcome was assessed using the modified Rankin Scale (mRS), with good and poor outcomes defined as mRS 0‐2 and 3‐6, respectively. HT was classified using ECASS criteria. The relationships between sST2, outcome, and HT were evaluated using multivariable logistic regression, Kaplan–Meier survival analysis and receiver operating characteristic curves.Results646 patients were included in the analysis (mean age 69 years; 44% women), with a median NIHSS of 5 [IQR: 2–12]. The median sST2 level on hospital admission was 35.0 ng/mL [IQR: 25.7–49.8 ng/mL] and at 48 h it was 37.4 ng/mL [IQR 27.9–55.6 ng/mL]. sST2 was independently associated with poor outcome (OR: 2.77, 95% CI: 1.54–5.06; P = 0.003) and mortality (OR: 3.56, 95% CI: 1.58–8.38, P = 0.001) after multivariable adjustment. Plasma sST2 was also associated with hemorrhagic transformation after adjustment for traditional risk factors (OR: 5.58, 95% CI: 1.40–37.44, P = 0.039).InterpretationSoluble ST2 may serve as a prognostic biomarker for outcome and hemorrhagic transformation in patients with acute stroke. ST2 may link neuroinflammation and secondary injury after stroke.

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Immunomodulation by interleukin-33 is protective in stroke through modulation of inflammation

Cited by 111 publications

References 56 publications

Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke

Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke

Therapeutic Strategies for Targeting IL-33/ST2 Signalling for the Treatment of Inflammatory Diseases

Soluble ST2 predicts outcome and hemorrhagic transformation after acute stroke

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