Production and functions of IL-33 in the central nervous system

Yasuoka, Satoko; Koyama, Jun; Parajuli, Bijay; Jin, Shijie; Doi, Yukiko; Noda, Mariko; Sonobe, Yoshifumi; Takeuchi, Hideyuki; Mizuno, Tetsuya; Suzumura, Akio

doi:10.1016/j.brainres.2011.02.045

Cited by 179 publications

(268 citation statements)

References 34 publications

Supporting

Mentioning

256

Contrasting

Order By: Relevance

“…A previous report [30] suggested that ST2 is expressed by the astrocytes based on ST2 gene transcript in the cultured cells. Using immunohistochemical staining in CNS tissues, we show here that ST2 protein is exclusively expressed by the neuron cells in the spinal cord, but not the GFAP + astrocytes in situ, whereas IL-33 protein is expressed by both neuron cells and astrocytes, in agreement with an earlier report [36]. Thus, IL-33 may function in an autocrine and a paracrine manner.…”

Section: Discussionsupporting

confidence: 91%

IL‐33 attenuates EAE by suppressing IL‐17 and IFN‐γ production and inducing alternatively activated macrophages

et al. 2012

View full text Add to dashboard Cite

Interleukin (IL)- [26] and is a proinflammatory cytokine in CIA [14,27]. Recent studies have also shown that the IL-33/ST2 pathway plays a significant role in the amplification of M2 polarization and chemokine production, which contribute to innate and antigen-induced airway inflammation [28] and protect against obesity-related metabolic events [29].Interestingly, the highest levels of IL-33 expression in naïve mice are found in the brain and spinal cord [15], indicating that IL-33 may have CNS-specific functions in addition to its role in immune modulation. Astrocytes express both and the expression of IL-33 in the CNS was increased in response to inflammatory stimuli [31]. Recently, it was also reported that IL-33 levels were elevated in the periphery and CNS of MS patients, implicating IL-33 in the pathogenesis of MS [32]. However, the precise role of IL-33 and its receptor in CNS under healthy and inflammatory conditions remain unclear.In the present study, we show that ST2 1C). Quantitative PCR analysis confirmed the upregulation of ST2 expression in Fig. 1B as it clearly shows the enhanced expression of ST2 mRNA in the CNS of mice with EAE compared with that of the naïve mice (Fig. 1D). ST2 −/− mice developed exacerbated EAETo identify an endogenous role of IL-33 in EAE, we next investigated the development of EAE in ST2 −/− mice. EAE was induced in C57BL/6 WT and ST2 −/− mice, Fig. 2A shows that the ST2 −/− mice developed more severe EAE than that in the WT mice. In agreement with many previous reports, BALB/c mice are resistant to the induction of EAE. However ST2 −/− BALB/c mice developed a mild but clearly detectable EAE while the WT BALB/c controls did not (Fig. 2B), the observation was further confirmed by histological analysis of the CNS tissues at day 19 after immunization ( Fig. 2C). Minimal leukocyte infiltration was found in the CNS of WT BALB/c mice whereas significant leukocyte infiltration was found in the submeningeal infiltration in the CNS tissues of ST2 −/− BALB/c mice ( Fig. 2C). IL-33 treatment attenuates EAE developmentWe next investigated the effect of exogenous IL-33 in the development of EAE. C57BL/6 mice were immunized as described in was injected intraperitoneally to each mouse daily from day 12 to day 20 after immunization. Both groups of mice developed similar degree of EAE from day 10 to day 15. However, from day 15, mice treated with IL-33 recovered significantly faster than the control mice treated with PBS ( Fig. 3A). In induced experimental autoimmune diseases, disease severity could vary between experiments even with the same protocol. Analysis using multiple comparisons suggests that the effect of IL-33 treatment on the outcome of EAE mice could be time revealed marked reduction of infiltrating cells in the spinal cord tissues of IL-33-treated mice (Fig. 3B). Importantly, IL-33 had no effect on the disease development in ST2 −/− C57BL/6 mice ( Fig. 3C) demonstrating the specificity of the IL-33 effect. IL-33 alters the cytokine production of EAE miceTo investigate the i...

show abstract

Section: Discussionsupporting

confidence: 91%

IL‐33 attenuates EAE by suppressing IL‐17 and IFN‐γ production and inducing alternatively activated macrophages

et al. 2012

View full text Add to dashboard Cite

show abstract

“…The ligand for ST2, IL‐33, is hypothesized to serve as an acute inflammatory signaling molecule that participates in maintaining barrier function and integrity 34. Isoforms of ST2 and IL‐33 are highly expressed in the brain and spinal cord, suggesting that IL‐33/ST2 may function directly in the central nervous system 12. In a murine model of stroke, IL‐33 signaling through the membrane‐bound form of ST2 has been shown to be neuroprotective through anti‐inflammatory effects 35.…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, sST2 is highly expressed in astrocytes and microglia, two cells types that may participate in the postischemic inflammatory response 12. However, no clinical study to date has evaluated the role of sST2 after ischemic stroke in patients.…”

Section: Introductionmentioning

confidence: 99%

Soluble ST2 predicts outcome and hemorrhagic transformation after acute stroke

Wolcott

Batra

Bevers

et al. 2017

Ann Clin Transl Neurol

View full text Add to dashboard Cite

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.

show abstract

“…It is intriguing that mast cell-derived IL-9 induces intestinal permeability and predisposes to oral antigen hypersensitivity in children (Forbes et al, 2008), while it also exacerbates newborn brain toxic lesions (Dommergues et al, 2000). Moreover, IL-33 can synergize with SP and SCF (Drube et al, 2010) in stimulating mast cell TNF release, while it also activates glial cells to secrete proinflammatory cytokines (Yasuoka et al, 2011). The possible involvement of mast cells in ASD is also supported by the fact that many children with ASD report "allergic-like" symptoms .…”

Section: Wwwintechopencommentioning

confidence: 98%