title: 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 β2-adrenergic receptor (β2AR) on murine alveolar macrophages and augment the release of IL-6. In mice, β2AR signaling promoted the development of a prothrombotic state that was sufficient to accelerate arterial thrombosis. In primary human alveolar macrophages, administration of a β2AR 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 β2AR on murine alveolar macrophages attenuated PM-induced IL-6 release and prothrombotic state. Furthermore, exogenous β2AR 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 β2AR signaling with metabolism, lung inflammation, and an enhanced susceptibility to thrombotic cardiovascular events.
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Chiarella
authors.forename: Saul
authors.initials: S
authors.lastname: Soberanes
authors.forename: Daniela
authors.initials: D
authors.lastname: Urich
authors.forename: Luisa
authors.initials: L
authors.lastname: Morales-Nebreda
authors.forename: Recep
authors.initials: R
authors.lastname: Nigdelioglu
authors.forename: David
authors.initials: D
authors.lastname: Green
authors.forename: James B
authors.initials: JB
authors.lastname: Young
authors.forename: Angel
authors.initials: A
authors.lastname: Gonzalez
authors.forename: Carmen
authors.initials: C
authors.lastname: Rosario
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Misharin
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Ghio
authors.forename: Richard G
authors.initials: RG
authors.lastname: Wunderink
authors.forename: Helen K
authors.initials: HK
authors.lastname: Donnelly
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Radigan
authors.forename: Harris
authors.initials: H
authors.lastname: Perlman
authors.forename: Navdeep S
authors.initials: NS
authors.lastname: Chandel
authors.forename: G R Scott
authors.initials: GR
authors.lastname: Budinger
authors.forename: Gökhan M
authors.initials: GM
authors.lastname: Mutlu
mesh_terms: D000262:Adenylyl Cyclases / Q000096:biosynthesis; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage* / Q000009:adverse effects*; D000818:Animals; D000990:Antithrombin III / Q000096:biosynthesis; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002395:Catecholamines / Q000096:biosynthesis; D005576:Colforsin / Q000008:administration & dosage; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D052638:Particulate Matter / Q000008:administration & dosage* / Q000009:adverse effects*; D010447:Peptide Hydrolases / Q000096:biosynthesis; D011433:Propranolol / Q000008:administration & dosage / Q000009:adverse effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000172:deficiency / Q000235:genetics; D018342:Receptors, Adrenergic, beta-1 / Q000172:deficiency / Q000235:genetics; D013927:Thrombosis / Q000209:etiology*
chemical_list: C547788:Adrb1 protein, mouse; D058666:Adrenergic beta-2 Receptor Agonists; D002395:Catecholamines; C508600:IL6 protein, human; D015850:Interleukin-6; D052638:Particulate Matter; D017382:Reactive Oxygen Species; D011943:Receptors, Adrenergic, beta; D018342:Receptors, Adrenergic, beta-1; C046193:antithrombin III-protease complex; D005576:Colforsin; D000990:Antithrombin III; D011433:Propranolol; D010447:Peptide Hydrolases; D000262:Adenylyl Cyclases