Early Brain Injury and Soluble ST2 After Nontraumatic Subarachnoid Hemorrhage

Schleicher, Riana; Bevers, Matthew B; Rubin, Daniel B.; Koch, Matthew J.; Bache, Søren; Lissak, India A.; Rosenthal, Eric S.; Møller, Kirsten; Kimberly, W. Taylor

doi:10.1161/strokeaha.121.035372

Cited by 3 publications

(4 citation statements)

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“…These findings are consistent with prior work in ischemic stroke 19 and subarachnoid hemorrhage 22,23 where sST2 was associated with secondary injury in the form of hemorrhagic transformation or delayed cerebral ischemia, respectively. The current study also reinforces the importance of the ST2-IL33 system in immune regulation after acute brain injury.…”

Section: Discussionsupporting

confidence: 92%

“…Recent work has identified soluble ST2 (sST2), a regulator of interleukin (IL)-33 signaling, as a potent marker of outcome and secondary injury in ischemic stroke [19][20][21] and subarachnoid hemorrhage. [22][23][24] The sST2 acts as a negative regulator of IL-33 by blocking signaling through the transmembrane ST2 (tmST2) receptor and modulates downstream immune responses. 25 An animal model of IPH has shown that administration of recombinant IL-33 reduces neurologic deficits, whereas injection of sST2 has the opposite effect.…”

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confidence: 99%

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Association of Soluble ST2 With Functional Outcome, Perihematomal Edema, and Immune Response After Intraparenchymal Hemorrhage

Bevers

Booraem

et al. 2023

Neurology

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Background and Objectives:Perihematomal edema (PHE) contributes to poor outcome after deep intraparenchymal hemorrhage (IPH), which is characterized by neuroinflammation and an influx of peripherally derived innate immune cells. We previously identified soluble ST2 (sST2) as a candidate for immune-mediated secondary brain injury. Leveraging prospectively collected cohorts from two centers, we sought to determine if sST2 was associated with functional outcome, PHE and the immune response following IPH.Methods:Patients with deep IPH were enrolled within 36 hours of ictus and blood was collected for sST2 and immune cell measurement. Hematoma volume and PHE were measured on serial CT scans. Good outcome was defined as modified Rankin Scale 0-3 at 90 days. Linear mixed effects models were used to analyze the relationship between sST2 and PHE over time. Flow cytometry was used to identify shifts in immune cell populations associated with sST2. Immunohistochemistry of human brain tissue was used to identify ST2-expressing cells in the perihematomal region.Results:The 55 included patients had median admission GCS of 14 [IQR 9-15], ICH score of 1 [IQR 1-2], and hematoma volume of 8.6mL [IQR 3.4-13.8]. Receiver operating curve analysis found sST2 level to be predictive of poor outcome with an area under the curve of 0.763 (95% CI 0.632 – 0.894) and Youden’s optimum cut point of 61.8ng/mL (p< 0.001). sST2 remained an independent predictor after adjustment for ICH score (adjusted OR 2.53 [95% CI 1.03-6.19],p= 0.042). Measurement of PHE found those patients with high sST2 to have greater edema volume over time (β = 1.07 [95% CI 0.51-1.63],p< 0.001). High sST2 was associated with a shift towards an innate peripheral immune response (monocytes and NK cells; 68.6±5.1% vs. 47.5±4.0%;p= 0.003).Discussion:Our findings demonstrate that elevated sST2 links the peripheral innate immune response to PHE volume and outcome after IPH. This knowledge is relevant to future studies that seek to identify IPH patients at highest risk for immune-mediated injury or limit injury through targeted interventions.

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Section: Discussionsupporting

confidence: 92%

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confidence: 99%

Association of Soluble ST2 With Functional Outcome, Perihematomal Edema, and Immune Response After Intraparenchymal Hemorrhage

Bevers

Booraem

et al. 2023

Neurology

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“…Multiple pathophysiological processes occurring after SAH, including early brain injury (EBI), cerebral vasospasm, and delayed cerebral ischaemia (1). Till now, mounting evidence has demonstrated that the neurological outcome after SAH is seriously influenced by early brain injury (EBI) (2)(3)(4). Multiple cellular mechanisms are involved in the EBI pathophysiology after SAH.…”

Section: Introductionmentioning

confidence: 99%

Takinib inhibits microglial M1 polarization and oxidative damage after subarachnoid hemorrhage by targeting TAK1-dependent NLRP3 inflammasome signaling pathway

Wang,

Pang,

Zhang

et al. 2023

Front. Immunol.

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Transforming growth factor-β-activated kinase 1 (TAK1) positively regulates oxidative stress and inflammation in different diseases. Takinib, a novel and specific TAK1 inhibitor, has beneficial effects in a variety of disorders. However, the effects of takinib on early brain injury (EBI) after subarachnoid hemorrhage (SAH) and the underlying molecular mechanisms remain unknown. Our study showed that takinib administration significantly inhibited phosphorylated TAK1 expression after SAH. In addition, takinib suppressed M1 microglial polarization and promoted M2 microglial polarization. Furthermore, blockade of TAK1 by takinib reduced neuroinflammation, oxidative damage, brain edema, and neuronal apoptosis, and improved neurological behavior after SAH. Mechanistically, we revealed that TAK1 inhibition by takinib mitigated reactive oxygen species (ROS) production and ROS-mediated nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome activation. In contrast, NLRP3 activation by nigericin abated the neuroprotective effects of takinib against EBI after SAH. In general, our study demonstrated that takinib could protect against EBI by targeting TAK1-ROS-NLRP3 inflammasome signaling. Inhibition of TAK1 might be a promising option in the management of SAH.

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“…Indeed, previous studies showed involvement of ST2-IL33 pathway in patients with ischemic stroke, subarachnoid hemorrhage (SAH), and other neurologic disorders including neurodegenerative diseases. [6][7][8] The answers are not clear. Given that sST2 is highly expressed in the brain and spinal cord, 8 and in this study brain macrophages expressed sST2, one may hypothesize that elevation of sST2 in peripheral blood was due to leakage from damaged BBB resulting in a chain of proinflammatory reactions.…”

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confidence: 99%