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Differential polarization and activation dynamics of systemic T helper cell subsets after aneurysmal subarachnoid hemorrhage (SAH) and during post-SAH complications.

ABSTRACT: Aneurysmal subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality. Devastating post-SAH complications, such as cerebral vasospasm (CVS), delayed cerebral ischemia or seizures to mention a few, are mainly responsible for the poor clinical outcome. Inflammation plays an indispensable role during early brain injury (EBI) and delayed brain injury (DBI) phases over which these complications arise. T helper cells are the major cytokine secreting cells of adaptive immunity that can polarize to multiple functionally unique sub-populations. Here, we investigate different CD4+ T cell subsets during EBI and DBI phases after SAH, and their dynamics during post-SAH complications. Peripheral venous blood from 15 SAH patients during EBI and DBI phases, was analyzed by multicolour flowcytometry. Different subsets of CD3+ CD4+ T cells were characterized by differential cell surface expression of CXCR3 and CCR6 into Th1, Th2, Th17, whereas Tregs were defined by CD25^hiCD127^lo. The analysis of activation states was done by the expression of stable activation markers CD38 and HLA-DR. Interestingly, compared to healthy controls, Tregs were significantly increased during both EBI and DBI phases. Different activation states of Tregs showed differential significant increase during EBI and DBI phases compared to controls. HLA-DR- CD38+ Tregs were significantly increased during DBI phase compared to EBI phase in SAH patients developing CVS, seizures and infections. However, HLA-DR- CD38- Tregs were significantly reduced during EBI phase in patients with cerebral ischemia (CI) compared to those without CI. HLA-DR- CD38- Th2 cells were significantly increased during EBI phase compared to controls. A significant reduction in Th17/Tregs and HLA-DR- CD38+ Th17/Tregs ratios was observed during both EBI and DBI phases compared to controls. While HLA-DR- CD38- Th17/Tregs and HLA-DR- CD38- Th1/Th2 ratios were impaired only during EBI phase compared to controls. In conclusion, CD4+ T cell subsets display dynamic and unique activation patterns after SAH and during the course of the manifestation of post-SAH complications, which may be helpful for the development of precision neurovascular care. However, to claim this, confirmatory studies with larger patient cohorts, ideally from different ethnic backgrounds, are required. Moreover, our descriptive study may be the grounds for subsequent lab endeavors to explore the underlying mechanisms of our observations.

SUBMITTER: Chaudhry SR

PROVIDER: S-EPMC8270974 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Aneurysmal subarachnoid hemorrhage (aSAH) is still a fatal and morbid disease, although bleeding aneurysms can be secured in almost all cases. Occurrence of post-SAH complications including cerebral vasospasm, delayed cerebral ischemia, hydrocephalus, epilepsy, and infections are the main determinants of clinical outcome. Hence, it is important to search for early predictors for specific post-SAH complications to treat these complications properly. Both cellular and molecular (cytokines) inflammation play a key role after aSAH during the phase of occurrence of post-SAH complications. Interleukin-6 (IL-6) is a well-known cytokine that has been extensively analyzed in cerebrospinal fluid (CSF) of patients after aSAH, but detailed studies exploring the role of systemic IL-6 in aSAH associated complications and its impact on early clinical outcome prediction are lacking. The current study aims to analyze the systemic IL-6 levels over two weeks after bleeding and its role in post-SAH complications. Methods: We recruited 80 aSAH patients prospectively who underwent peripheral venous blood withdrawal in serum gel tubes. The blood was centrifuged to harvest the serum, which was immediately frozen at -80 °C until analysis. Serum IL-6 levels were quantified using Immulite immunoassay system. Patient records including age, gender, post-SAH complications, aneurysm treatment, and clinical outcome (modified Rankin scale and Glasgow outcome scale) were retrieved to allow different subgroup analysis. Results: Serum IL-6 levels were significantly raised after aSAH compared to healthy controls over the first two weeks after hemorrhage. Serum IL-6 levels were found to be significantly elevated in aSAH patients presenting with higher Hunt and Hess grades, increasing age, and both intraventricular and intracerebral hemorrhage. Interestingly, serum IL-6 was also significantly raised in aSAH patients who developed seizures, cerebral vasospasm (CVS), and chronic hydrocephalus. IL-6 levels were sensitive to the development of infections and showed an increase in patients who developed pneumoniae. Intriguingly, we found a delayed increase in serum IL-6 in patients developing cerebral infarction. Finally, IL-6 levels were significantly higher in patients presenting with poor clinical outcome in comparison to good clinical outcome at discharge from hospital. Conclusion: Serum IL-6 levels were elevated early after aSAH and remained high over the two weeks after initial bleeding. Serum IL-6 was elevated in different aSAH associated complications, acting as a non-specific marker for post-SAH complications and an important biomarker for clinical outcome at discharge.

Project description:BackgroundAneurysmal subarachnoid hemorrhage (aSAH) leads to a robust systemic inflammatory response. We hypothesized that an early systemic glycolytic shift occurs after aSAH, resulting in a unique metabolic signature and affecting systemic inflammation.MethodsControl patients and patients with aSAH were analyzed. Samples from patients with aSAH were collected within 24 h of aneurysmal rupture. Mass spectrometry-based metabolomics was performed to assess relative abundance of 16 metabolites involved in the tricarboxylic acid cycle, glycolysis, and pentose phosphate pathway. Principal component analysis was used to segregate control patients from patients with aSAH. Dendrograms were developed to depict correlations between metabolites and cytokines. Analytic models predicting functional outcomes were developed, and receiver operating curves were compared.ResultsA total of 122 patients with aSAH and 38 control patients were included. Patients with aSAH had higher levels of glycolytic metabolites (3-phosphoglycerate/2-phosphoglycerate, lactate) but lower levels of oxidative metabolites (succinate, malate, fumarate, and oxalate). Patients with higher clinical severity (Hunt-Hess Scale score ≥ 4) had higher levels of glyceraldehyde 3-phosphate and citrate but lower levels of α-ketoglutarate and glutamine. Principal component analysis readily segregated control patients from patients with aSAH. Correlation analysis revealed distinct clusters in control patients that were not observed in patients with aSAH. Higher levels of fumarate were associated with good functional outcomes at discharge (odds ratio [OR] 1.76, 95% confidence interval [CI] 1.15-2.82) in multivariable models, whereas higher levels of citrate were associated with poor functional outcomes at discharge (OR 0.36, 95% CI 0.16-0.73) and at 3 months (OR 0.35, 95% CI 0.14-0.81). No associations were found with delayed cerebral ischemia. Levels of α-ketoglutarate and glutamine correlated with lower levels of interleukin-8, whereas fumarate was associated with lower levels of tumor necrosis factor alpha.ConclusionsAneurysmal subarachnoid hemorrhage results in a unique pattern of plasma metabolites, indicating a shift toward glycolysis. Higher levels of fumarate and lower levels of citrate were associated with better functional outcomes. These metabolites may represent targets to improve metabolism after aSAH.

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Differential polarization and activation dynamics of systemic T helper cell subsets after aneurysmal subarachnoid hemorrhage (SAH) and during post-SAH complications.

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