β2-Adrenergic agonists augment air pollution–induced IL-6 release and thrombosis

Abstract

Acute exposure to particulate matter (PM) air pollution causes thrombotic cardiovascular events, leading to increased mortality rates; however, the link between PM and cardiovascular dysfunction is not completely understood. We have previously shown that the release of IL-6 from alveolar macrophages is required for a prothrombotic state and acceleration of thrombosis following exposure to PM. Here, we determined that PM exposure results in the systemic release of catecholamines, which engage the β 2 -adrenergic receptor (β 2 AR) on murine alveolar macrophages and augment the release of IL-6. In mice, β 2 AR signaling promoted the development of a prothrombotic state that was sufficient to accelerate arterial thrombosis. In primary human alveolar macrophages, administration of a β 2 AR agonist augmented IL-6 release, while the addition of a beta blocker inhibited PM-induced IL-6 release. Genetic loss or pharmacologic inhibition of the β 2 AR on murine alveolar macrophages attenuated PM-induced IL-6 release and prothrombotic state. Furthermore, exogenous β 2 AR agonist therapy further augmented these responses in alveolar macrophages through generation of mitochondrial ROS and subsequent increase of adenylyl cyclase activity. Together, these results link the activation of the sympathetic nervous system by β 2 AR signaling with metabolism, lung inflammation, and an enhanced susceptibility to thrombotic cardiovascular events.

β2-Adrenergic receptors in immunity and inflammation: Stressing NF-κB

“…Also, a recent study exploring the influence of air pollution on the expression of IL-6 showed that particulate matter potentiated sympathetic tone, which enhanced NF-jB-mediated transcription of IL-6 in human and murine alveolar macrophages, resulting in a prothrombotic state and accelerated arterial thrombosis. Importantly, b 2 -agonist administration mimicked the effect of stress catecholamines on IL-6 expression (Chiarella et al, 2014). Finally, we and others (Table 2) observed that not only IL-6 expression, but also that of several chemokines, is potentiated in different cell types in response to cotreatment with a pro-inflammatory stimulus and a b 2 -agonist.…”

Reply: β2-Agonists and Acute Respiratory Distress Syndrome

“…Alternatively, the activation of b 2 ARs in other cells in the lung may negate the beneficial effects of their activation in the alveolar epithelium. For example, we have recently shown that b 2 -agonist therapy worsens lung inflammation in a murine model of lung injury via engagement of b 2 ARs on macrophages (10). We agree with the authors that additional studies will be needed to distinguish the beneficial effects of b 2 ARs from their unwanted and harmful effects.…”

Response by Li et al to Letters Regarding Article, “Particulate Matter Exposure and Stress Hormone Levels: A Randomized, Double-Blind, Crossover Trial of Air Purification”

“…Consistent with our findings, Kodavanti 5 reviewed current evidence on the neuroendocrine effects of air pollution and suggested that stress hormones, including catecholamine and glucocorticoids, are involved in physical responses of air pollution exposures and may contribute to increased risk of diseases. Also, a recent study by Chiarella et al 6 reported a significant increase of norepinephrine in lung, adrenal gland and brown adipose tissues with drastic fold changes in animal models after exposure to concentrated ambient particles. Our findings on norepinephrine and the findings in the study by Zevin et al 7 may not be comparable because the response to stimulation from environment factors could be different between healthy, nonsmoking college students and heavy smokers.…”