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Effects of CNS Injury-Induced Immunosuppression on Pulmonary Immunity

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Effects of CNS Injury-Induced Immunosuppression on Pulmonary Immunity life Review Effects of CNS Injury-Induced Immunosuppression on Pulmonary Immunity Bashir Bietar * , Christian Lehmann and Andrew W. Stadnyk Departments of Microbiology and Immunology, Pharmacology, Pediatrics and Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; [email protected] (C.L.); [email protected] (A.W.S.) * Correspondence: [email protected] Abstract: Patients suffering from stroke, traumatic brain injury, or other forms of central nervous sys- tem (CNS) injury have an increased risk of nosocomial infections due to CNS injury-induced immuno- suppression (CIDS). Immediately after CNS-injury, the response in the brain is pro-inflammatory; however, subsequently, local and systemic immunity is suppressed due to the compensatory release of immunomodulatory neurotransmitters. CIDS makes patients susceptible to contracting infections, among which pneumonia is very common and often lethal. Ventilator-acquired pneumonia has a mortality of 20–50% and poses a significant risk to vulnerable patients such as stroke survivors. The mechanisms involved in CIDS are not well understood. In this review, we consolidate the evidence for cellular processes underlying the pathogenesis of CIDS, the emerging treatments, and speculate further on the immune elements at play. Keywords: immunosuppression; CNS-injury; stroke; pneumonia; lung Citation: Bietar, B.; Lehmann, C.; 1. Introduction Stadnyk, A.W. Effects of CNS The main conditions responsible for central nervous system (CNS) injury are trauma, Injury-Induced Immunosuppression stroke, and spinal cord injuries. Traumatic brain injury (TBI) is one of the leading causes on Pulmonary Immunity. Life 2021, of morbidity and mortality worldwide in individuals under the age of 45 years. Globally, 11, 576. https://doi.org/10.3390/ stroke is the second leading cause of death, with 5.5 million deaths per year. Further- life11060576 more, stroke results in up to 50% of survivors being chronically disabled [1]. The primary mechanisms of TBI are classified as focal or global (multi-focal) brain damage. Focal brain Academic Editor: Candice M. Brown damage can be caused by injuries of mechanical origin such as car accidents, force from blunt objects, or gunshot wounds. Focal injury pathologies include cerebral lacerations Received: 12 May 2021 and contusions and various types of hemorrhages. Multi-focal brain damage is due to Accepted: 15 June 2021 Published: 18 June 2021 acceleration/deceleration injuries such as concussions, which result in diffuse axonal in- jury, ischemic brain injury, or brain swelling [2]. Stroke can be the result of ischemic or Publisher’s Note: MDPI stays neutral hemorrhagic events in the brain. In this review, when referring to stroke it will be in with regard to jurisdictional claims in relation to ischemic stroke, which is a focal brain injury due to cerebral blood flow arrest to published maps and institutional affil- a particular area of the brain, resulting in rapid local cell death. iations. The major pathophysiological sequelae of cerebral injury after TBI and stroke is a consequence of direct hypoxic damage to the tissue. Due to terminal membrane depolar- ization caused by the excessive release of neurotransmitters, voltage-dependent calcium and sodium channels are activated, leading to catabolic intracellular processes mediated by nucleases, lipases, and proteases, which disrupt and degrade membranes and proteins. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. The upregulation of calcium and sodium levels in ischemic cells stimulate disproportionate This article is an open access article reactive oxygen species (ROS) production, which directly damage proteins, lipids, carbo- distributed under the terms and hydrates, and nucleic acids [3]. Ultimately, this cascade will result in a complex mix of conditions of the Creative Commons neuronal and vascular cell death by necrosis, apoptosis, and autophagy. The response of Attribution (CC BY) license (https:// the immune system to these events includes local inflammation governed by the resting creativecommons.org/licenses/by/ microglia. The microglia becomes activated, releasing soluble mediators including pro- 4.0/). inflammatory cytokines and chemokines such as TNF, IL-1ß, IL-6, CCL2-CCL5, and CXCL8 Life 2021, 11, 576. https://doi.org/10.3390/life11060576 https://www.mdpi.com/journal/life Life 2021, 11, x FOR PEER REVIEW 2 of 12 microglia. The microglia becomes activated, releasing soluble mediators including pro- inflammatory cytokines and chemokines such as TNF, IL-1ß, IL-6, CCL2-CCL5, and CXCL8 following injury [4]. These mediators upregulate leukocyte adhesion molecules such as intercellular adhesion molecule (ICAM)-1 and P-selectin, and endothelial cell vas- cular adhesion molecule (VCAM)-1. This ensures that activated leukocytes adhere to en- dothelial cells and infiltrate injured tissue. In general, the end goal for the local immune response is to eliminate cellular debris and repair salvageable tissue [3]. Following, and despite this initial state of local immune activation, the immune re- sponse outside the CNS is found to be suppressed and thought to be a major contributor to nosocomial infections that often occur to survivors of CNS injury. The pathophysiology Life 2021, 11, 576 of CNS injury leads to the release of local immunomodulatory factors2 ofthat 12 activate the sympathetic (SNS) and parasympathetic nervous systems (PNS) and the hypothalamic- pituitary-adrenal axis (HPA). This activation causes the release of a variety of neuromod- following injury [4]. These mediators upregulate leukocyte adhesion molecules such as ulatorsintercellular including adhesion catecholamines molecule (ICAM)-1 (CA), and acetylcholine P-selectin, and (AC) endothelial, and cell glucocorticoids vascular (GC), which actadhesion on the molecule primary (VCAM)-1. and secondary This ensures that lymphoid activated leukocytesorgans, adherealtering to endothelial immune cell function and cytokinecells and production. infiltrate injured The tissue. consequence In general, the endis generally goal for the localdecreasing immune responseproduction is of pro-in- to eliminate cellular debris and repair salvageable tissue [3]. flammatoryFollowing, cytokines and while despite increasing this initial state anti of- localinflammatory immune activation, cytokines the immune such as re- IL-10. The net effect issponse systemic outside theimmunosuppression CNS is found to be suppressed (Figure and thought1) [5]. to Patients be a major contributorin this condition to are at higher nosocomialrisk of nosocomial infections that infections. often occur to A survivors common of CNS infection injury. The that pathophysiology affects patient of s with CNS CNS injury leads to the release of local immunomodulatory factors that activate the sympa- injury isthetic nosocomial (SNS) and parasympathetic pneumonia. nervousExperimental systems (PNS) studies and the have hypothalamic-pituitary- shown that activated micro- glia changeadrenal their axis (HPA).morphology This activation from causes the ramified the release oftoward a variety the of neuromodulatorshypertrophic or amoeboid phenotypesincluding in catecholaminesresponse to (CA), CNS acetylcholine injury. The (AC), accumulation and glucocorticoids of (GC), hypertrophic which act on or amoeboid the primary and secondary lymphoid organs, altering immune cell function and cytokine microgliaproduction. was correlated The consequence with neurogenic is generally decreasing acute lung production injury in of pro-inflammatoryrats with neurotrauma. Fur- thermore,cytokines there while is evidence increasing anti-inflammatorythat links viral cytokines or bacterial such as lung IL-10. infection The net effect, to is activating the microgliasystemic in the immunosuppression paraventricular (Figure nucleus1)[ 5 (PVN)]. Patients of in hypothalamus, this condition are atwhich higher leads risk to increased of nosocomial infections. A common infection that affects patients with CNS injury is hypothalamicnosocomial IL pneumonia.-6 expression Experimental and exacerbated studies have shown neuroinflammation that activated microglia [6,7] change. The predisposi- tion of theirTBI, morphology stroke, and from spinal the ramified cord towardinjury the patients hypertrophic to pneumonia or amoeboid phenotypesleads to greater in morbid- ity andresponse increases to CNS mortality injury. The rates. accumulation Understandably, of hypertrophic interest or amoeboid has g microgliarown in was the relationship correlated with neurogenic acute lung injury in rats with neurotrauma. Furthermore, there betweenis evidencethis state that of links immunosuppression viral or bacterial lung infection,and the to patients’ activating response the microglia to in pneumonia. the paraventricular nucleus (PVN) of hypothalamus, which leads to increased hypothalamic IL-6 expression and exacerbated neuroinflammation [6,7]. The predisposition of TBI, stroke, and spinal cord injury patients to pneumonia leads to greater morbidity and increases mortality rates. Understandably, interest has grown in the relationship between this state of immunosuppression and the patients’ response to pneumonia. Figure 1. A graphical representation of immune dysregulation following central nervous system (CNS) injury (modified according to Zhou et al., 2019 [8]). This review will compare the healthy lung immune response with the immunosup- pressed patient lung immune status and speculate on the mechanisms by which immuno- Figure 1. A graphical
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