Interleukin-6 Receptor Signalling and Abdominal Aortic Aneurysm Growth Rates

Abstract

Objective: The Asp358Ala variant (rs2228145; A>C) in the interleukin-6 receptor (IL6R) gene has been implicated in the development of abdominal aortic aneurysms (AAAs), but its effect on AAA growth over time is not known. We aimed to investigate the clinical association between the IL6R-Asp358Ala variant and AAA growth, and to assess the effect of blocking the IL-6 signalling pathway in mouse models of aneurysm rupture. Approach: Using data from 2,863 participants with AAA from nine prospective cohorts, ageand sex-adjusted mixed-effects linear regression models were used to estimate the association between the IL6R-Asp358Ala variant and annual change in AAA diameter (mm/year). In a series of complementary randomised trials in mice, the effect of blocking the IL-6 signalling pathways was assessed on plasma biomarkers, systolic blood pressure, aneurysm diameter and time to aortic rupture and death. Results: After adjusting for age and sex, baseline aneurysm size was 0.55mm (95% confidence interval [CI]: 0.13, 0.98mm) smaller per copy of the minor allele [C] of the Asp358Ala variant. There was no evidence of a reduction in AAA growth rate (change in growth=-0.06mm per year [-0.18, 0.06] per copy of the minor allele). In two mouse models of AAA, selective blockage of the IL-6 trans-signalling pathway, but not combined blockage of both, the classical and trans-signalling pathways, was associated with improved survival (p<0.05). Conclusions:Our proof-of-principle data are compatible with the concept that IL-6 transsignalling is relevant to AAA growth, encouraging larger-scale evaluation of this hypothesis.

Galectin-3 as a Biomarker for Stratifying Abdominal Aortic Aneurysm Size in a Taiwanese Population

“…Plasma Gal-3 levels were significantly higher in patients with AAA than in control patients (96.9 ± 4.5L vs. 76.5 ± 1.9 ng/mL, Figure 1A). In this sample set, we analyzed the plasma concentrations of IL-6, which is reportedly associated with AAA (7,19,20). The levels of IL-6 were higher in AAA samples than in healthy control samples (92.8 ± 5.2 pg/mL vs. 72.5 ± 3.0 pg/mL; Figure 1B).…”

“…IL-6 has a critical role in elevating the circulating concentrations of several plasma proteins, including fibrinogen and C-reactive protein (CRP). Therefore, IL-6 has been identified as an essential pro-inflammatory cytokine in the pathogenesis of AAA (7,19,20). However, the prognostic value of IL-6 is controversial.…”

POU class 2 homeobox associating factor 1 (POU2AF1) participates in abdominal aortic aneurysm enlargement based on integrated bioinformatics analysis

“…In past decades, studies have implicated crucial roles of various inflammatory cells, including T cells, B cells, macrophages, dendritic cells, neutrophils, and mast cells, etc, as well as their intercellular communications and cytokines secretion abilities in AAA initiation and progression 65 . Moreover, complex cellular signaling pathways, such as NF-κB 66 , TGF-β 67 , MAPK 68 , Notch 69 and IL-6 70 comprehensively analyzed profiles of infiltrated immune cells in AAA tissues and their associated marker genes, which provided insights into the underlying mechanisms of AAA formation and progression regarding to immune infiltration. The current study focused on exploring the up-regulated key genes in AAA enlargement and progression, thus, microarray datasets with detailed sample diameter information were included.…”

Gut microbiome sheds light on the development and treatment of abdominal aortic aneurysm

“…Moreover, Sirtuin1 can effectively block NF-κB and MCP-1 from initiating an inflammatory response in VSMCs, representing an important target for preventing the formation of AAA (139). Besides, selectively blocking IL-6 signal transduction with sgp130 can improve the survival rate of AAA mice (140). Cilostazol could reduce macrophage accumulation, MMPs activation, and inflammatory gene expression in the aortic media, which may be a promising new therapeutic option for inhibiting the occurrence and growth of AAA (141).…”