Abstract
Following our recent report that phagocytic cells (neutrophils, PMNs, and macrophages) are newly discovered sources of catecholamines, we now show that both epinephrine and norepinephrine directly activate NFκB in macrophages, causing enhanced release of proinflammatory cytokines (TNFα, IL-1β, IL-6). Both adrenal-intact (AD+) and adrenalectomized (ADX) rodents were used, because ADX animals had greatly enhanced catecholamine release from phagocytes, facilitating our efforts to understand the role of catecholamines released from phagocytes. Phagocytes isolated from adrenalectomized rats displayed enhanced expression of tyrosine-hydroxylase and dopamine-β-hydroxylase, two key enzymes for catecholamine production and exhibited higher baseline secretion of norepinephrine and epinephrine. The effects of upregulation of phagocyte-derived catecholamines were investigated in two models of acute lung injury (ALI). Increased levels of phagocyte-derived catecholamines were associated with intensification of the acute inflammatory response, as assessed by increased plasma leak of albumin, enhanced myeloperoxidase content in lungs, augmented levels of proinflammatory mediators in bronchoalveolar lavage fluids, and elevated expression of pulmonary ICAM-1 and VCAM-1. In adrenalectomized rats, development of ALI was enhanced and related to α2-adrenoceptors engagement but not to involvement of mineralocorticoid or glucocorticoid receptors. Collectively, these data demonstrate that catecholamines are potent inflammatory activators of macrophages, upregulating NFκB and further downstream cytokine production of these cells. In adrenalectomized animals, which have been used to further assess the role of catecholamines, there appears to be a compensatory increase in catecholamine generating enzymes and catecholamines in macrophages, resulting in amplification of the acute inflammatory response via engagement of α2-adrenoceptors.
Highlights
During an immune response, the central nervous system and the immune system communicate with each other [1]
This suggests induction of intracellular proinflammatory pathways by norepinephrine and epinephrine. To evaluate if this catecholamine-induced activation of NFkB was followed by increased downstream production of proinflammatory cytokines, peritoneal mouse macrophages were incubated for 4 hrs at 37uC with either HBSS, LPS
Immune mediators and cytokines released by the innate immune system rapidly activate neuronal responses, resulting in amplified local immune responses designed to clear pathogens and triggering regional neural and systemic neuroendocrine responses, both of which seek to return the system to a homeostatic state [1]
Summary
The central nervous system and the immune system communicate with each other [1]. Activation of the vagus-dominated parasympathetic, cholinergic nervous system is known to greatly attenuate and dampen the inflammatory response via nicotinergic cholinergic receptors expressed on macrophages and other immune cells [4,5]. SNS activation seems to target immune cells that express adrenoreceptors, exacerbating the local inflammatory response [7,8], and increase the general immune and proinflammatory mediator response [9,10,11]. Several studies indicate an inhibitory effect of the SNS on the inflammatory response, suppressing the immune response by decreasing the activity of natural killer cells and T cell immunity [12,13,14,15]. Catecholamines released from presynaptic sympathetic nerve terminals lead to localized vasoconstriction, preventing invading pathogens from becoming systemic [3]
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