Cholinergic Pathway Suppresses Pulmonary Innate Immunity Facilitating Pneumonia After Stroke

Abstract

T he management of medical complications is one of the most critical factors in the therapy of stroke because 95% of stroke patients experience at least one relevant medical complication in the first 3 months after stroke. 1 In both experimental and clinical studies, infections are the most common complication after stroke.2 Among these, pneumonia is the most relevant poststroke infection, 3 accounting for the highest attributable mortality after stroke. 4 To maintain body homeostasis in response to challenges from the environment, the nervous and immune systems are closely interconnected in an intense bidirectional communication. 5 Recent experimental and clinical evidence indicates that central nervous system injuries like stroke, spinal cord injury, or traumatic brain injury disturb the normally well-balanced interplay between these 2 supersystems, resulting in a profound and long-lasting immunodepression. 6,7 Overactivation of the sympathetic nervous system after stroke was shown to mediate suppression of peripheral cellular immune responses and to contribute to development of poststroke bacterial lung infections. [8][9][10] However, changes in the pulmonary immune compartment and the underlying mechanisms of impaired antibacterial lung immune responses after stroke are currently not understood.Besides resident lung immune cells, such as alveolar macrophages (MΦ), alveolar epithelial cells (AEC) express Background and Purpose-Temporary immunosuppression has been identified as a major risk factor for the development of pneumonia after acute central nervous system injury. Although overactivation of the sympathetic nervous system was previously shown to mediate suppression of systemic cellular immune responses after stroke, the role of the parasympathetic cholinergic anti-inflammatory pathway in the antibacterial defense in lung remains largely elusive. Methods-The middle cerebral artery occlusion model in mice was used to examine the influence of the parasympathetic nervous system on poststroke immunosuppression. We used heart rate variability measurement by telemetry, vagotomy, α7 nicotinic acetylcholine receptor-deficient mice, and parasympathomimetics (nicotine, PNU282987) to measure and modulate parasympathetic activity. Results-Here, we demonstrate a rapidly increased parasympathetic activity in mice after experimental stroke. Inhibition of cholinergic signaling by either vagotomy or by using α7 nicotinic acetylcholine receptor-deficient mice reversed pulmonary immune hyporesponsiveness and prevented pneumonia after stroke. In vivo and ex vivo studies on the role of α7 nicotinic acetylcholine receptor on different lung cells using bone marrow chimeric mice and isolated primary cells indicated that not only macrophages but also alveolar epithelial cells are a major cellular target of cholinergic antiinflammatory signaling in the lung. 12 Both MΦ and lung epithelial cells have been shown to express the α7 nicotinergic acetylcholine receptor (α7nAChR), 13 which has been identified as a crucial downstre...

Potential specific immunological indicators for stroke associated infection are partly modulated by sympathetic pathway activation

“…Although experimental studies have proven stroke-induced immunodepression by showing decreased peripheral IL-6 production, numerous clinical studies have found that IL-6 expression actually increases after stroke in response to strong inflammatory reactions induced by ischaemic brain injury [28–30]. Our results suggest that very strong inflammatory responses occur in SAI patients which activate anti-inflammatory feedback causing increased IL-10.…”

The Efficacy of Prophylactic Antibiotics on Post-Stroke Infections: An Updated Systematic Review and Meta-Analysis

“…The most likely explanation is that post-stroke pneumonia may be a respiratory syndrome resulting from multiple factors, including medical complications and complex bacterial, chemical, and immunological causes that might not be preventable with antibiotics alone1421. For example, acute stroke may lead to stroke-induced immunodepression by the cholinergic pathway, reducing lymphocyte count and delaying the recovery of T-lymphocyte loss, which may promote stroke patients developing post-stroke pneumonia222324. More importantly, other existing preventive measures such as positioning, regular suction, swallowing techniques and modified diets may also be essential for patients with suspected post-stroke pneumonia in specialist stroke units25.…”

Ischaemic stroke and the recanalization drug tissue plasminogen activator interfere with antibacterial phagocyte function

“…These immune alterations are thought to be initialized by high concentrations of catecholamines and glucocorticoids, which are regularly observed post-stroke in mice and in humans [5–9]. In animal models, inhibition of the sympathetic nervous system by propranolol or interruption of the parasympathetic nervous system by vagotomy reversed lymphocytic dysfunction and lowered the incidence of bacteraemia and pneumonia, whereas blocking the hypothalamus-pituitary gland axis by Ru486 normalised lymphocyte numbers and HLA-DR expression in monocytes [10, 11]. We previously reported that the oxidative burst, a mechanism that produces free oxygen radicals to kill phagocytosed bacteria, is impaired in ischaemic stroke patients in both granulocytes and monocytes.…”