Activation of the sympathetic nervous system modulates neutrophil function

Abstract

One sentence summary: Sympathetic activation of neutrophils significantly impairs several critical host defense functions, including chemotaxis, phagocytosis and neutrophil-endothelial cell interactions. AbstractEmerging evidence has revealed that noradrenaline (NA), the main neurotransmitter of the sympathetic nervous system (SNS), regulates a variety of immune functions via binding to adrenergic receptors present on immune cells. In this study, we examined the role of NA in the regulation of neutrophil functions. Neutrophils were isolated from the bone marrow of naïve mice and treated with NA at various concentrations to assess the effect on various neutrophil functions.Additionally, we performed cremaster intravital microscopy to examine neutrophil-endothelial cell interactions following NA superfusion in vivo. In a separate group of animals, mice were subjected to an experimental model of stroke and at 4 and 24 h neutrophils were isolated for assessment on their ability to migrate toward various chemokines. Treatment of neutrophils with NA for 4 h significantly impaired neutrophil chemotaxis and induced an N2 neutrophil phenotype with reduced expression of the genes critical for cytoskeleton remodeling and inflammation. Prolonged NA administration promoted neutrophils to release myeloperoxidase and IL-6, but suppressed the production of interferon-and IL-10, reduced neutrophil activation and phagocytosis. Superfusion of NA over the cremaster muscle almost completely inhibited fMLP-induced neutrophil adhesion/arrest and transmigration. Furthermore, using a mouse model of stroke, a pathological condition in which SNS activation is evident, neutrophils isolated from poststroke mice showed markedly reduced chemotaxis toward all of the chemokines tested. The findings from our study indicate that neutrophil chemotaxis, activation, and phagocytosis can all be negatively regulated in an NA-dependent manner. A better understanding of the relationship between sympathetic activation and neutrophil function will be important for the development of effective antibacterial interventions.

Ischemic stroke alters immune cell niche and chemokine profile in mice independent of spontaneous bacterial infection

“…A recent study has shown that neutrophils from the mouse bone marrow have an impaired chemotactic ability poststroke in an in vitro model. 9 However, neutrophil infiltration to the lungs was observed in both spontaneous-or aspiration-induced pneumonia following tMCAO. 3,5 We observed an increase in alveolar macrophages and the infiltration of neutrophils in the lungs following tMCAO, but their bacterial clearance capability remains to be elucidated.…”

“…Our data suggested that alterations in the pulmonary immune cell niche following ischemic stroke may partly explain the lung‐specific immunodeficiency. A recent study has shown that neutrophils from the mouse bone marrow have an impaired chemotactic ability poststroke in an in vitro model . However, neutrophil infiltration to the lungs was observed in both spontaneous‐ or aspiration‐induced pneumonia following tMCAO .…”

“…Current knowledge of the immunological responses following stroke were mostly generated using the murine transient middle cerebral artery occlusion (tMCAO) model of ischemic stroke induction. So far, immune phenotypes that are linked to stroke‐induced immunosuppression include (a) induction of apoptosis of lymphocytes (T cells, B cells, and natural killer [NK] cells) in the blood, spleen, and the thymus; (b) reduced expression of proinflammatory tumour necrosis factor (TNF) but increased expression of immunosuppressive interleukin‐10 (IL‐10) in blood and splenic monocytes; (c) reduction of interferon γ (IFN‐γ) expression in blood T cells and liver natural killer T (NKT) cells; and (d) impaired neutrophil chemotaxis . Among these mechanisms, the reduction of IFN‐γ in liver NKT cells seems to be the most relevant, as propranolol treatment in mice following ischemic stroke restores IFN‐γ production in these cells .…”

“…So far, immune phenotypes that are linked to stroke-induced immunosuppression include (a) induction of apoptosis of lymphocytes (T cells, B cells, and natural killer [NK] cells) in the blood, spleen, and the thymus 3 ; (b) reduced expression of proinflammatory tumour necrosis factor (TNF) but increased expression of immunosuppressive interleukin-10 (IL-10) in blood and splenic monocytes 7 ; (c) reduction of interferon γ (IFN-γ) expression in blood T cells and liver natural killer T (NKT) cells 3,8 ; and (d) impaired neutrophil chemotaxis. 9 Among these mechanisms, the reduction of IFN-γ in liver NKT cells seems to be the most relevant, as propranolol treatment in mice following ischemic stroke restores IFN-γ production in these cells. 8 However, currently there is no explanation for how immune cell defects occurring in remote organs, such as the liver and the spleen, lead to bacterial infection in the lungs.…”

Stress hormone signaling through β‐adrenergic receptors regulates macrophage mechanotype and function

“…Immune cells sense and integrate information from diverse environmental cues (1)(2)(3). In response to physiologic and psychologic stressors, fibers of the peripheral sympathetic nervous system release catecholaminergic stress hormones including norepinephrine into major organ systems to induce a "fight-or-flight" response; epinephrine is released from the adrenal gland into circulation (4,5). Norepinephrine and epinephrine bind to b-adrenergic receptors (b-ARs) to mediate changes in immune cell function.…”