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

47 Citations (Scopus)

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

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Adrenergic Agonists
Particulate Matter
Air Pollution
Alveolar Macrophages
Interleukin-6
Thrombosis
Adrenergic Receptors
Sympathetic Nervous System
Adenylyl Cyclases
Catecholamines
Pneumonia
Mortality

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Chiarella, S. E., Soberanes, S., Urich, D., Morales-Nebreda, L., Nigdelioglu, R., Green, D., ... 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
Chiarella, Sergio E. ; Soberanes, Saul ; Urich, Daniela ; Morales-Nebreda, Luisa ; Nigdelioglu, Recep ; Green, David ; Young, James B. ; Gonzalez, Angel ; Rosario, Carmen ; Misharin, Alexander V. ; Ghio, Andrew J. ; Wunderink, Richard G. ; Donnelly, Helen K. ; Radigan, Kathryn A. ; Perlman, Harris ; Chandel, Navdeep S. ; Budinger, G. R.Scott ; Mutlu, Gökhan M. / β2-Adrenergic agonists augment air pollution-induced IL-6 release and thrombosis. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 7. pp. 2935-2946.
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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.",
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Chiarella, SE, Soberanes, S, Urich, D, Morales-Nebreda, L, Nigdelioglu, R, Green, D, Young, JB, Gonzalez, A, Rosario, C, Misharin, AV, Ghio, AJ, Wunderink, RG, Donnelly, HK, Radigan, KA, Perlman, H, Chandel, NS, Budinger, GRS & Mutlu, GM 2014, 'β2-Adrenergic agonists augment air pollution-induced IL-6 release and thrombosis', Journal of Clinical Investigation, vol. 124, no. 7, pp. 2935-2946. https://doi.org/10.1172/JCI75157

β2-Adrenergic agonists augment air pollution-induced IL-6 release and thrombosis. / Chiarella, Sergio E.; Soberanes, Saul; Urich, Daniela; Morales-Nebreda, Luisa; Nigdelioglu, Recep; Green, David; Young, James B.; Gonzalez, Angel; Rosario, Carmen; Misharin, Alexander V.; Ghio, Andrew J.; Wunderink, Richard G.; Donnelly, Helen K.; Radigan, Kathryn A.; Perlman, Harris; Chandel, Navdeep S.; Budinger, G. R.Scott; Mutlu, Gökhan M.

In: Journal of Clinical Investigation, Vol. 124, No. 7, 01.07.2014, p. 2935-2946.

Research output: Contribution to journalArticle

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T1 - β2-Adrenergic agonists augment air pollution-induced IL-6 release and thrombosis

AU - Chiarella, Sergio E.

AU - Soberanes, Saul

AU - Urich, Daniela

AU - Morales-Nebreda, Luisa

AU - Nigdelioglu, Recep

AU - Green, David

AU - Young, James B.

AU - Gonzalez, Angel

AU - Rosario, Carmen

AU - Misharin, Alexander V.

AU - Ghio, Andrew J.

AU - Wunderink, Richard G.

AU - Donnelly, Helen K.

AU - Radigan, Kathryn A.

AU - Perlman, Harris

AU - Chandel, Navdeep S.

AU - Budinger, G. R.Scott

AU - Mutlu, Gökhan M.

PY - 2014/7/1

Y1 - 2014/7/1

N2 - 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.

AB - 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.

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Chiarella SE, Soberanes S, Urich D, Morales-Nebreda L, Nigdelioglu R, Green D et al. β2-Adrenergic agonists augment air pollution-induced IL-6 release and thrombosis. Journal of Clinical Investigation. 2014 Jul 1;124(7):2935-2946. https://doi.org/10.1172/JCI75157