Adrenergic and Glucocorticoid Receptors in the Pulmonary Health Effects of Air Pollution

Abstract

Adrenergic receptors (ARs) and glucocorticoid receptors (GRs) are activated by circulating catecholamines and glucocorticoids, respectively. These receptors regulate the homeostasis of physiological processes with specificity via multiple receptor subtypes, wide tissue-specific distribution, and interactions with other receptors and signaling processes. Based on their physiological roles, ARs and GRs are widely manipulated therapeutically for chronic diseases. Although these receptors play key roles in inflammatory and cellular homeostatic processes, little research has addressed their involvement in the health effects of air pollution. We have recently demonstrated that ozone, a prototypic air pollutant, mediates pulmonary and systemic effects through the activation of these receptors. A single exposure to ozone induces the sympathetic-adrenal-medullary and hypothalamic-pituitary-adrenal axes, resulting in the release of epinephrine and corticosterone into the circulation. These hormones act as ligands for ARs and GRs. The roles of beta AR (βARs) and GRs in ozone-induced pulmonary injury and inflammation were confirmed in a number of studies using interventional approaches. Accordingly, the activation status of ARs and GRs is critical in mediating the health effects of inhaled irritants. In this paper, we review the cellular distribution and functions of ARs and GRs, their lung-specific localization, and their involvement in ozone-induced health effects, in order to capture attention for future research.

Keywords: adrenergic receptors; air pollution; glucocorticoid receptors; inflammation; lung injury; ozone.

Figure 1

A flow chart of how air pollutant exposure through the neuroendocrine pathways activates adrenergic (ARs) and glucocorticoid receptors (GRs) and influences pulmonary response. Upon inhalation, air pollutants likely activate autonomic sensory nerves, which relay stress signals to the hypothalamus though the brainstem. This stimulates the hypothalamus to induce changes in the neuroendocrine pathways, including the activation of SAM and HPA axes, which results in release of catecholamines, such as epinephrine, and cortisol/corticosterone, into circulation. These hormones mediate their effects through widely distributed receptors for catecholamines (ARs) and glucocorticoids (GRs). These receptors—in addition to mediating homeostatic changes in physiological processes, and diurnal variations—respond to air pollution stress and direct bodily immune and metabolic responses at the site of injury. These processes result in a local inflammatory response that is governed by multiple organs, including the brain. IL-6: interleukin 6; TLR2: toll-like receptor 2; TLR4: toll-like receptor 4.

Figure 2

Schematic showing the cellular effects of activating AR subtypes in the lung. The left panel shows the distribution of α₁AR, β₂AR and GR in lung cells. The right panel shows cell signaling through α₁AR and β₂AR. β₂AR signaling involves cAMP-mediated activation of PKA through phosphorylation, and effects on transcription factors that mediate the expression of genes regulating bronchodilation, inflammation, and epithelial transport. α₁AR signaling, on the other hand, leads to increases in intracellular free calcium though the activation of phospholipase C and diacylglycerol, where the activation of PKC causes pulmonary vasoconstriction. β₂AR: beta 2 adrenergic receptors; α₁AR: alpha 1 adrenergic receptors; ATP: adenosine triphosphate; cAMP: cyclic adenosine monophosphate; PKA: protein kinase A.

Figure 3

A schematic of lung cellular effects from activating GRs. Lipophilic glucocorticoids enter cells freely. Upon entering cells, glucocorticoids bind to GRs, which exist in the cytoplasm complexed with heat shock proteins 70 and 90 (Hsp70 and Hsp90), p23, and other proteins, such as steroid receptor coactivator (SRC). Upon binding to glucocorticoids, other proteins are recruited in the complex, preparing it for nuclear translocation. Once in the nucleus, GRs recruit P300/CBP-associated factor (pCAF), CREB-binding protein (CBP), and histone acetyltransferase (HAT), allowing complex to modify the chromatin framework and bind to glucocorticoid response elements (GREs) in promotor sequences of DNA. This results in transactivation or transrepression, leading to activation or inhibition of gene transcription. This is achieved through the direct binding of the GR complex to GREs and/or its interaction with other transcription factors (some details are not given in the figure for simplicity). Through their transcriptional regulation of gene expression, GRs change the expression of genes involved in inflammation, acute-phase response, and anti-inflammatory mechanisms. GILZ: glucocorticoid-induced leucine zipper; MT-1: metallothionein-1; SGK: serine/threonine-protein kinase.

Figure 4

Proposed schematic of how adrenergic and glucocorticoid mechanisms regulate circadian changes and environmental stress signals to direct immune responses with oscillatory patterns. The suprachiasmatic nucleus (SCN), receiving photonic signals from the retina via the retinohypothalamic tract, transmits these to the paraventricular nucleus (PVN) of the hypothalamus, which also integrates other stress signals from afferent autonomic sensory nerves, including those induced by pulmonary encountered air-pollution-induced stress. These signals are integrated in the hypothalamus and relayed to the periphery through: (1) sympathetic nerves, which transmit signals to the peripheral organs by releasing norepinephrine (NE); (2) sympathetic nerves innervating the adrenal medulla and regulating the production and release of epinephrine (EPI) and norepinephrine into circulation; and (3) the hypothalamus–pituitary–adrenal (HPA) axis mediating the pituitary release of adrenocorticotropic hormone (ACTH), and then stimulating glucocorticoid (GC) production by the adrenal cortex. Adrenal glucocorticoids locally regulate the release of medullary hormones. Catecholamines and glucocorticoids released into circulation induce pulsatile cellular physiological changes resulting from stress and circadian rhythms through binding to their receptors—AR and GR subtypes, respectively. Within the central nervous system, the locus coeruleus (LC) produces norepinephrine, which is transmitted across many brain regions, including the SCN, and can regulate circadian changes centrally. Circulating catecholamines and glucocorticoids bind to ARs and GRs in diverse organs and cells, including immune cells, to regulate the expression of the circadian locomotor output cycles kaput (CLOCK) and brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1) regulated genes. The signaling involves the activation of transcription factors, including the cyclic AMP response element-binding protein (CREB), to modulate the expression of CLOCK and BMAL1-regulated genes. The CLOCK and BMAL1 transcription factors regulate the transcription of genes encoding circadian proteins, such as period circadian proteins (PERs) and cryptochromes (CRY). The rhythmic activation of GRs upon binding to GCs, and their nuclear translocation, can modulate gene expression for inflammatory processes in association with CLOCK and BLAM1 in immune cells that facilitate diurnal changes in maturation and homing of immune cells and inflammation.