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??-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 ?2-adrenergic receptor (?2AR) on murine alveolar macrophages and augment the release of IL-6. In mice, ?2AR signaling promoted the development of a prothrombotic state that was sufficient to accelerate arterial thrombosis. In primary human alveolar macrophages, administration of a ?2AR 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 ?2AR on murine alveolar macrophages attenuated PM-induced IL-6 release and prothrombotic state. Furthermore, exogenous ?2AR 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 ?2AR signaling with metabolism, lung inflammation, and an enhanced susceptibility to thrombotic cardiovascular events.

SUBMITTER: Chiarella SE

PROVIDER: S-EPMC4071386 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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

Chiarella Sergio E SE Soberanes Saul S Urich Daniela D Morales-Nebreda Luisa L Nigdelioglu Recep R Green David D Young James B JB Gonzalez Angel A Rosario Carmen C Misharin Alexander V AV Ghio Andrew J AJ Wunderink Richard G RG Donnelly Helen K HK Radigan Kathryn A KA Perlman Harris H Chandel Navdeep S NS Budinger G R Scott GR Mutlu Gökhan M GM

The Journal of clinical investigation 20140527 7

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 ...[more]

PMID: 24865431

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Project description:BackgroundThe NF-?B signaling pathway orchestrates many of the intricate aspects of neuroinflammation. Astrocytic ??-adrenergic receptors have emerged as potential regulators in central nervous system inflammation and are potential targets for pharmacological modulation. The aim of this study was to elucidate the crosstalk between astrocytic ??-adrenergic receptors and the TNF-? induced inflammatory gene program.MethodsProinflammatory conditions were generated by the administration of TNF-?. Genes that are susceptible to astrocytic crosstalk between ??-adrenergic receptors (stimulated by clenbuterol) and TNF-? were identified by qPCR-macroarray-based gene expression analysis in a human 1321 N1 astrocytoma cell line. Transcriptional patterns of the identified genes in vitro were validated by RT-PCR on the 1321 N1 cell line as well as on primary rat astrocytes. In vivo expression patterns were examined by intracerebroventricular administration of clenbuterol and/or TNF-? in rats. To examine the impact on the inflammatory cell content of the brain we performed extensive FACS analysis of rat brain immune cells after intracerebroventricular clenbuterol and/or TNF-? administration.ResultsParallel transcriptional patterns in vivo and in vitro confirmed the relevance of astrocytic ??-adrenergic receptors as modulators of brain inflammatory responses. Importantly, we observed pronounced effects of ?2-adrenergic receptor agonists and TNF-? on IL-6, CXCL2, CXCL3, VCAM1, and ICAM1 expression, suggesting a role in inflammatory brain cell homeostasis. Extensive FACS-analysis of inflammatory cell content in the brain demonstrated that clenbuterol/TNF-? co-administration skewed the T cell population towards a double negative phenotype and induced a shift in the myeloid brain cell population towards a neutrophilic predominance.ConclusionsOur results show that astrocytic ??-adrenergic receptors are potent regulators of astrocytic TNF-?-activated genes in vitro and in vivo, and ultimately modulate the molecular network involved in the homeostasis of inflammatory cells in the central nervous system. Astrocytic ??-adrenergic receptors and their downstream signaling pathway may serve as potential targets to modulate neuroinflammatory responses.

Dataset Information

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

Publications

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

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