Interactions between the Autonomic Nervous System and the Immune System after Stroke

Abstract

Acute stroke is one of the leading causes of morbidity and mortality worldwide. Stroke-induced immune-inflammatory response occurs in the perilesion areas and the periphery. Although strokeinduced immunosuppression may alleviate brain injury, it hinders brain repair as the immuneinflammatory response plays a bidirectional role after acute stroke. Furthermore, suppression of the systemic immune-inflammatory response increases the risk of life-threatening systemic bacterial infections after acute stroke. Therefore, it is essential to explore the mechanisms that underlie the stroke-induced immune-inflammatory response. Autonomic nervous system (ANS) activation is critical for regulating the local and systemic immune-inflammatory responses and may influence the prognosis of acute stroke. We review the changes in the sympathetic and parasympathetic nervous systems and their influence on the immune-inflammatory response after stroke. Importantly, this article summarizes the mechanisms on how ANS regulates the immune-inflammatory response through neurotransmitters and their receptors in immunocytes and immune organs after stroke.To facilitate translational research, we also discuss the promising therapeutic approaches modulating the activation of the ANS or the immune-inflammatory response to promote neurologic recovery after stroke.

Premorbid Use of Beta-Blockers or Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers in Patients with Acute Ischemic Stroke

“…Regulatory T cells (Treg) and alternatively activated macrophages (phenotype similar to M2) may exhibit immunosuppressive and neuroprotective effects after ischemic stroke [ 52 , 53 ]. Activation of the sympathetic nervous system induced by ischemic stroke could reduce the frequency of circulating lymphocytes [ 10 ]. Studies also illustrated that catecholamines increased the frequency of circulating Treg cells and promoted the polarization of circulating macrophages to an alternatively activated M2-like (anti-inflammatory) phenotype in the acute phase of ischemic stroke [ 41 , 54 ].…”

“…The hypothalamic-pituitary-adrenal axis activation by ischemic stroke also increased cortisol secretion from the adrenal tract. Subsequently, it promoted apoptosis of B lymphocytes in peripheral blood [ 10 , 41 ]. A previous study illustrated that using beta-blockers to block peripheral sympathetic nerves did not reverse the effects on the frequency of B lymphocytes in the peripheral blood of mice with transient middle cerebral artery occlusion (tMCAO).…”

“…Additionally, increased sympathetic activity is associated with worse outcomes in patients with ischemic stroke [ 10 ]. Beta-blockers could inhibit hyperactivation of the sympathetic system and reverse chronic heart failure-induced lymphopenia [ 21 ].…”

“…Inflammation is essential in the pathophysiological process of ischemic stroke [7][8][9][10]. Evidence has indicated that increased sympathetic activity induced by ischemic stroke may contribute to the poststroke alteration of the systemic immune system, including changes in the percentages or counts of circulating neutrophils, lymphocytes, and monocytes [10][11][12][13][14]. On the contrary, alterations in the cellular immune system affect the outcomes of patients with acute ischemic stroke [10,15].…”

“…Evidence has indicated that increased sympathetic activity induced by ischemic stroke may contribute to the poststroke alteration of the systemic immune system, including changes in the percentages or counts of circulating neutrophils, lymphocytes, and monocytes [10][11][12][13][14]. On the contrary, alterations in the cellular immune system affect the outcomes of patients with acute ischemic stroke [10,15]. A previous study has reported that stroke-induced sympathetic nervous system hyperactivity increased hematopoietic stem and progenitor cell activity in the bone marrow, consequently increasing neutrophil and monocyte counts in peripheral blood [16].…”