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

Sergio E. Chiarella, Saul Soberanes, Daniela Urich, Luisa Morales-Nebreda, Recep Nigdelioglu, David Green, James B. Young, Angel Gonzalez, Carmen Rosario, Alexander V. Misharin, Andrew J. Ghio, Richard G. Wunderink, Helen K. Donnelly, Kathryn A. Radigan, Harris Perlman, Navdeep S. Chandel, G. R.Scott Budinger, Gökhan M. Mutlu*

*Corresponding author for this work

Research output: Contribution to journalArticle

60 Scopus citations

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 β22-adrenergic receptor (β22AR) on murine alveolar macrophages and augment the release of IL-6. In mice, β22AR signaling promoted the development of a prothrombotic state that was sufficient to accelerate arterial thrombosis. In primary human alveolar macrophages, administration of a β22AR 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 β22AR on murine alveolar macrophages attenuated PM-induced IL-6 release and prothrombotic state. Furthermore, exogenous β22AR 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 β22AR signaling with metabolism, lung inflammation, and an enhanced susceptibility to thrombotic cardiovascular events.

Original languageEnglish (US)
Pages (from-to)2935-2946
Number of pages12
JournalJournal of Clinical Investigation
Volume124
Issue number7
DOIs
StatePublished - Jul 1 2014

ASJC Scopus subject areas

  • Medicine(all)

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    Chiarella, S. E., Soberanes, S., Urich, D., Morales-Nebreda, L., Nigdelioglu, R., Green, D., Young, J. B., Gonzalez, A., Rosario, C., Misharin, A. V., Ghio, A. J., Wunderink, R. G., Donnelly, H. K., Radigan, K. A., Perlman, H., Chandel, N. S., Budinger, G. R. S., & Mutlu, G. M. (2014). β2-Adrenergic agonists augment air pollution-induced IL-6 release and thrombosis. Journal of Clinical Investigation, 124(7), 2935-2946. https://doi.org/10.1172/JCI75157