Plasma IL-33 in atopic patients correlates with pro-inflammatory cytokines and changes cholesterol transport protein expression: a surprising neutral overall impact on atherogenicity.

Objective: Interleukin (IL)-33 has been associated with atopic and inflammatory conditions. IL-33 may be atheroprotective inducing a Th1-to-Th2 immunologic switch. However, the role of IL-33 in cardiovascular disease remains unclear. This study examines the effect of physiological and elevated IL-33 levels in plasma from atopic patients (AP) on cholesterol metabolism in human macrophages as compared to plasma from healthy controls (HC).

Methods: Twenty-five AP and 25 HC were enrolled in this study. Plasma samples were analysed for levels of IL-33, IFN-γ, TNF-α, IL-17α, IL-5 and soluble ST2. THP-1 differentiated macrophages were exposed to HC and AP plasma. Expression of proteins involved in reverse cholesterol transport (ABCA1, ABCG1 and 27-hydroxylase) and scavenger receptors, responsible for uptake of modified lipids (CD36, ScR-A1, CXCL16 and LOX-1), was measured using QRT-PCR and immunoblotting techniques.

Results: IL-33 was significantly higher in AP plasma: 106.7 ± 95 pg/mL versus HC plasma (53.4 ± 23 pg/mL). IL-33 concentration strongly correlated with levels of IFN-γ (r = 0.85), TNFα (r = 0.9) and IL-17α (r = 0.94). No significant difference was found in soluble ST2 levels. An important contrast was observed for 27-hydroxylase: normal IL-33 in AP plasma amplified 27-hydroxylase while increased IL-33 suppressed it. Expression of CD36 and SR-A1 was greater in macrophages exposed to plasma with high IL-33, while CXCL16 was higher in cells grown in the presence of plasma with normal IL-33.

Conclusions: Here, we demonstrate that high levels of IL-33 and a high IL-33/soluble ST2 ratio correlates with elevated levels of IFN-γ, TNF-α and IL-17α as well as IL-5, demonstrating that IL-33 has pleiotropic effects. However, elevated IL-33 did not significantly impact lipid accumulation in macrophages overall. Given the wide variety of cellular responses regulated by IL-33, further investigation with a larger sample size will allow us to clarify the threshold concentration of IL-33 that leads to optimal cholesterol balance.