Pro-Inflammatory and Anti-Inflammatory Cytokines Levels are Significantly Altered in Cerebrospinal Fluid of Unruptured Intracranial Aneurysm (UIA) Patients

Abstract

Introduction Identifying all the relevant “players” in the formation and development of brain aneurysms may help understand the mechanisms responsible for the formation of an aneurysm, as well as in the search for non-invasive targets for aneurysm pharmacotherapy. Aim The evaluation of the concentration of pro-inflammatory and anti-inflammatory cytokines in cerebrospinal fluid (CSF) and serum of patients with unruptured intracranial aneurysms (UIA) in comparison to individuals without vascular lesions in the brain. Methods The concentration of 27 proteins in the CSF and serum of UIA patients (N = 40) and individuals without vascular lesions in the brain (N = 15) was evaluated using a multiplex ELISA kit (Bio-Plex Pro Human Cytokine 27-Plex Panel). Results In the CSF 13 out of 27 proteins evaluated presented a concentration 1.36-fold or greater in UIA patients in comparison to the control group. Significantly higher were IL-1β, IL-1ra, IL-2, IL-4, IL-5, IL-7, IL-8, IL-12, IL-13, TNF-α, INF-γ, MCP-1, and VEGF. In the serum none of the proteins evaluated significantly differ between UIA patients and the control group. The correlation coefficient analysis showed that CSF IL-1β, IL-8, and TNF-α positively, while IL-13 negatively correlated with the size of aneurysms. CSF IL-6 and MCP-1 concentrations positively correlated with the number of aneurysms. Conclusion In patients with UIA, pro-inflammatory and anti-inflammatory mechanisms are activated simultaneously, because the concentration of promoting and suppressing inflammatory response proteins was significantly higher in CSF of UIA patients compared to the control group. The preventive therapy of brain aneurysm development should be focused on IL-1β, IL-6, IL-8, MCP-1, and TNF-α, the concentration of which in CSF positively correlated with the size and number of aneurysms.

Circulating Inflammatory Cytokines and Risk of Intracranial Aneurysm: A Mendelian-randomization Study

“…Identifying these affected inflammatory factors can enhance our comprehension of the regulatory mechanism of IA inflammation. Previous observational studies have demonstrated that the levels of IL-12p70, IL-4, IFNg, IL-10, IL-17, IL-1ra, IL-6, VEGF, and FGFBasic are positively correlated with the pathogenesis of IA, which is consistent with our findings (30,39,40,44,45). However, there still needs to be an observational study to clarify the association between IL9 and IA.…”

“…VEGF is a heparin-binding protein that regulates pathological angiogenesis by inducing vascular endothelial cell proliferation and migration, mediating endothelial injury in the IA wall (37,38). Observational studies have reported elevated VEGF levels in ruptured aneurysm tissue of aSAH patients and cerebrospinal fluid of UIA patients (39,40). Combined with our findings, it appears that VEGF primarily affects the process of aneurysm wall remodeling with IA.…”

Circulating inflammatory biomarkers and risk of intracranial aneurysm: a Mendelian randomization study

“…Plasma VEGF concentrations were found to be increased uIA patients compared with healthy controls, but statistical significance was restricted to male participants [ 43 ]. Controversial result was carried out by another study which did not identify significant difference of VEGF in plasma but rather in cerebrospinal fluid [ 44 ]. Experimental studies further indicated the role of VEGF-A in aneurysmal growth and rupture [ 45 , 46 ].…”

Potential application of peripheral blood biomarkers in intracranial aneurysms

“…Yang et al ( 23 ) prospectively collected preoperative blood samples from 184 UIA patients and divided them into high and low-risk groups based on propensity matching score and ELAPSS score; results showed patients with higher serum levels of IL-15, monocyte chemotactic protein-1 (MCP-1), and TNF-β were associated with an increased risk of aneurysm growth, and elevated IL-15 and TNF-β serum levels might indicate IA progression. Kamińska et al ( 24 ) analyzed 27 cytokines in the serum and CSF of UIA patients and compared them to those without IA. Results showed that cytokines in CSF might be locally synthesized within the central nervous system, reflecting inflammatory response at the site of aneurysms and more effective than serum in identifying IA formation and development.…”