Research progress in stroke-induced immunodepression syndrome (SIDS) and stroke-associated pneumonia (SAP)

https://doi.org/10.1016/j.neuint.2018.01.002Get rights and content

Highlights

  • The relation between the central nervous system and the immune system after stroke is expounded.

  • The cause and influencing factors of stroke associated pneumonia were systematically introduced.

  • The treatment directions of stroke associated pneumonia were pointed out in detail.

Abstract

In recent years, stroke-induced immunodepression syndrome (SIDS) and the resulting stroke-associated infection (SAI) have become a focus of current research efforts. Inflammatory reactions after stroke promote tissue healing and eliminate necrotic cells, whereas excessive inflammatory reactions may cause secondary damage. Stroke-induced immunodepression not only reduces inflammatory reactions and protects brain tissues but also weakens the resistance of the human body against pathogens and leads to infection. Changes in the local and systemic immune system in stroke patients may play an important role in prognosis. Infection is a leading cause of death in patients following stroke, and an evaluation of the prognosis of stroke patients is associated closely with the presence of infectious complications. Among these complications, pneumonia is the most common type of infection observed after acute stroke, which exhibits the greatest effect on the recovery of neurological function. SIDS is closely related to stroke-associated pneumonia (SAP), and the use of immunodepression as an entry point may provide an efficacious treatment target and drug development strategy. An improved understanding of the pathophysiological mechanisms leading to SAP is essential to develop new treatment strategies for improving the outcomes of stroke patients.

Introduction

As one of the most common cerebrovascular diseases, stroke has the characteristics of a high rate of incidence, mortality, disability and recurrence. The significant increase in stroke rates worldwide corresponds with the increase in the aging population. Stroke is divided into ischemic and haemorrhagic categories based on whether clogged blood vessels impede blood flow into the brain or blood vessels in the brain suddenly rupture. Acute ischemic stroke is the most common type, accounting for 80% of the total stroke cases (Macrez et al., 2011).

Many complications may occur after stroke, such as secondary infections, haemorrhagic transformation, epilepsy, sepsis, etc. According to its occurrence and development, stroke progression is divided into three periods (Bustamante et al., 2016). (1) Hyper-acute period. In this period, the most fatal complication is haemorrhagic transformation. The incidence of haemorrhagic transformation is 8.5%–30%, and the risk increases when patients use antithrombotic drugs, particularly anticoagulants or thrombolytic agents (Wang et al., 2015). (2) Sub-acute period. Several complications can occur during this period, such as acute gastrointestinal bleeding, increased intracranial pressure, dysphagia, seizures, epilepsy, stroke-associated infection (SAI), etc. (3) Chronic period. Pressure ulcer, pain, epilepsy, faecal and urinary incontinence, and depression are frequent sequelae in this period. Overall, the complications observed after stroke are mainly divided into two types: complications of the internal medicine system and neurological complications. Among the numerous complications, SAI has been shown to be the leading cause of death or disability (Miller and Behrouz, 2016) and is associated with higher rates of recurrence and subsequent readmission (Shah et al., 2015). SAI mainly includes stroke-associated pneumonia (SAP) and urinary tract infections, and the pooled overall infection rate is 30%. Urinary tract infection and SAP show a similar prevalence, whereas SAP is significantly associated with death (Westendorp et al., 2011). According to the results from a prospective study, SAI had long-lasting effects on the long-term survival of people who experienced a stroke within the last three years (Kwan et al., 2013). In particular, pneumonia increases the 30-day, 1-year (Ingeman et al., 2011) and 3-year (Yu et al., 2016) mortality. Thus, effective control of SAP is of substantial importance in improving the survival rate and quality of life of stroke patients.

Many factors influence SAP, such as age, the severity of ischemic, other concurrent diseases, and invasive operation, among others. However, based on accumulating evidence, changes in immunity triggered by an acute cerebral injury is the main cause of SAI (Chamorro et al., 2007). Acute stroke may lead to a nerve-immune system disorder, causing systemic immunodepression, which is not unique to stroke and also occurs after traumatic brain injury, spinal cord injury, brain surgery and other central nervous system (CNS) injuries (Meisel et al., 2005). The main clinical manifestations of stroke-induced immunodepression syndrome (SIDS) are the rapid and persistent depression of cellular immune function, deactivation of monocytes and Th1 cells, Th-mediated lymphopenia (Haeusler et al., 2008), and increased apoptosis of immune cells in the spleen, thymus and lymph nodes (Liesz et al., 2009, Prass et al., 2003). We focus on the aetiologies of SAP and highlight the key factors that influence SAP in this review to obtain a better understanding of this type of complication after stroke. We hope this review will provide more useful ideas and information for SAP research.

The interaction between the immune system and CNS is critical to the prognosis of stroke patients (Dirnagl et al., 2007). Pathogen invasion or some forms of injury induce cytokine release from immune cells. Then, the released cytokines are sensed by the afferent vagus nerve and effectively stimulate the immune regulatory centre (hypothalamus, etc.) to produce anti-inflammatory signals. Subsequently, the efferent vagus nerve is activated and inhibits cytokine production, resists infection and prevents deterioration (Johnston and Webster, 2009). An excessive, sustained inflammatory response may exhaust the immune system and ultimately lead to the suppression of systemic immunity, which is thought to protect the brain from further inflammatory insults after stroke. However, this suppression may predispose patients to SIDS and infections (Shim and Wong, 2016). As presented in the schematic shown in Fig. 1, SIDS is closely related to the activation of 3 systems: the sympathetic nervous system (SNS) (Winklewski et al., 2014, Yan and Zhang, 2014), the parasympathetic nervous system (PNS) (Dorrance and Fink, 2015) and the hypothalamus-pituitary-adrenal (HPA) axis (Radak et al., 2014).

The SNS is over-activated after stroke and then induces immunodepression through the β-arrestin2-NF-κB pathway (Deng et al., 2016) or the cAMP-PKA-NF-κB pathway (Zuo et al., 2016). Catecholamines are the principal effectors of the SNS and include epinephrine, norepinephrine and dopamine (El Husseini and Laskowitz, 2014). When the sympathetic adrenal medulla system is excited, catecholamine is released into the blood. A sustained increase in catecholamine levels reduces the number of circulating lymphocytes. The catecholamine-mediated defect in early lymphocyte activation plays an important role in the impaired antibacterial immune response after stroke (Prass et al., 2003).

The cholinergic anti-inflammatory pathway mainly includes the vagus nerve, spleen and α7 nicotinic acetylcholine receptor (α7 nAChR) (Martelli et al., 2014). The activated PNS activates the cholinergic neurotransmitter by secreting acetylcholine, which inhibits the release of peripheral inflammatory cytokines. The cholinergic anti-inflammatory pathway was recently shown to be associated with the neural immune mechanism and played a pivotal role in the development of SAP (Engel et al., 2015b). Previously, the activated PNS was shown to exert neuroprotective effects on ischemic stroke (Cheyuo et al., 2011). Delayed administration of varenicline, a high-affinity agonist for α7 nAChR and an established therapy for nicotine addiction, was recently reported to decrease brain inflammation and improve motor function in a mouse model of experimental stroke (Chen et al., 2017). Thus, strategies targeting the cholinergic anti-inflammatory pathway represent new methods for the prevention and treatment of stroke that do not cause immunodepression. However, it must be noted that excessive stimulation of the cholinergic pathway after stroke may exacerbate the risk of infections (Engel et al., 2015a).

The hypothalamus senses the production of inflammatory markers following stroke and activates the HPA axis; excessive glucocorticoids are then secreted from the zona fasciculata of the adrenal gland to induce lymphocytopenia and alter levels of inflammatory/anti-inflammatory mediators (Mracsko et al., 2014b, Offner et al., 2006a). Stroke patients with higher urinary cortisol levels were more susceptible to infections, which indirectly reflected a greater level of stroke-related stress and higher levels of glucocorticoids released into the blood (Kumar et al., 2014). Glucocorticoids have anti-inflammatory effects, whereas excessive glucocorticoid levels will reduce the body's defences and lead to immunodepression. Preadmission use of systemic glucocorticoids is associated with an increased short-term risk of mortality after stroke (Sundboll et al., 2016).

The SNS is responsible for SAI to a greater extent than the HPA axis (Mracsko et al., 2014b). The neuroendocrine system and the autonomic nervous system synchronize with each other via the paraventricular nucleus of the hypothalamus to realize changes in immune function after stroke (El Husseini and Laskowitz, 2014). Immunodepression rapidly occurs within 24 h after stroke onset and persists for weeks, whereas SAP usually occurs between days 1 and 7 (Harms et al., 2013). As a result of immunodepression, the ability of body to resist pathogens decreases after stroke. For example, nasal inoculation with only 200 colony-forming units of S. pneumoniae caused severe pneumonia in mice, whereas sham animals needed to be inoculated with several hundred-fold more colony-forming units to comparably induce pneumonia (Prass et al., 2006). The pathogenic bacteria that cause SAP are mostly Staphylococcus aureus and various gram-negative bacilli (Chang et al., 2013), which is one of the main reasons for the aggravation of complications and even the death of stroke patients. Good oral hygiene to decrease the colonization of various bacterial in sputum is important for preventing SAP (Wagner et al., 2015). In addition to SIDS, many other factors also affect SAP.

Stroke impairs the function of deglutition, which presents as an interruption in the voluntary control of mastication and bolus transport during the oral phase. This defect also causes dysphagia, which is involved in more than 50% of stroke patients (Mourao et al., 2016). Due to the synergistic effect of the laryngeal protective reflex and swallowing, food and foreign bodies generally do not readily enter the lower respiratory tract in normal humans. Dysphagia after stroke is mostly related to oropharyngeal dysfunction, and the significant feature of dysphagia is sluggish rather than reduced hyolaryngeal movements during swallowing (Seo et al., 2016). The prognosis of stroke patients with dysphagia is not good, as these patients have an 8.5-fold higher risk of death compared with patients with normal swallowing at 3 months post-stroke (Arnold et al., 2016). Dysphagia also causes other complications, such as aspiration pneumonia, malnutrition, dehydration and psychological disorders. Dysphagia is an important risk factor for pneumonia within the first day after stroke, and it increases the risk of pneumonia more than 3-fold among stroke patients and 11-fold in more severely impaired patients with confirmed aspiration (Martino et al., 2005). Dysphagia and SIDS are independent risk factors for SAP, and screens for dysphagia and immunodepression may be significant in determining the risk of pneumonia in stroke patients and in the implementation of routine, tailored, preventive measures for such patients in the clinic (Hoffmann et al., 2016). Currently, an early dysphagia screen is an effective way to reduce the risk of SAP (Al-Khaled et al., 2016). Notably, dysphagia may increase the risk of SAP, but dysphagia alone is not sufficient to induce SAP development (Masrur et al., 2013).

Stroke patients with severe cases are administered invasive treatments, such as endotracheal intubation, tracheotomy, and mechanical ventilation, among others. These treatments result in direct exposure of the respiratory system to the external environment, which will damage the respiratory mucosal barrier, hinder ciliary movement, accelerate the downward movement of the oropharyngeal bacteria, ultimately lead to lower respiratory tract infections (Sui and Zhang, 2011). When the host immune function is damaged or when the resident flora is disturbed, the colonizing bacteria multiply and cause diseases. Antacids, such as histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs), are used to reduce the concentration of gastric acid and to prevent and treat stress-related ulcers. Antacids may increase the bacterial colonization of the gastric cavity and promote retrograde transport to the oropharynx under certain conditions, leading to the occurrence of a pulmonary infection (Sui and Zhang, 2011). According to the results from a retrospective study, the choice of drug for gastric acid suppression had no effect on the incidence of pneumonia following acute stroke (Momosaki et al., 2016). However, PPIs were more closely associated with chronic SAP than acute SAP, and physicians should use caution when prescribing PPIs to patients with chronic stroke (Ho et al., 2015). In addition, the impact of SAP on the treatments and outcomes of acute stroke patients in a specialized NICU setting is remarkable (Hilker et al., 2003), which may be ascribed to the severe condition of the patients in NICUs.

Medical risk factors, such as hypertension, diabetes, pulmonary diseases, among others, predispose stroke patients to multiple organ failure and exacerbate infections. Considering all known factors, hypertension is more closely associated with the risk and severity of stroke. Hypertension affects approximately 1.4 billion people worldwide, and the incidence of essential hypertension steadily increases with age (Hisham and Bayraktutan, 2013). Hypertension causes various complications and often culminates in stroke. Approximately 80% of stroke cases are associated with hypertension and hypertension has significant effect on the residual lifetime risk of stroke (Turin et al., 2016). Severe hypertension upon admission is an independent predictive factor for SAP in elderly patients with acute ischemic stroke (Ishigami et al., 2012). The precise mechanism underlying the interaction between hypertension and SAP requires further elucidation, and some mechanisms have been proposed. (1) The excessive activation of SNS after stroke not only leads to immunodepression but also to severe hypertension. Early phase of acute ischemic stroke patients with severe hypertension have high mortality, poor functional prognosis, and promote the occurrence of SAP (Ishigami et al., 2012). (2) Chronic hypertension initiates intracerebral vasculopathy and accelerates the destruction of the blood-brain barrier (BBB) after stroke. For example, compared with normotensive Wistar-Kyoto (WKY) rats, spontaneously hypertensive (SHR) rats are more susceptible to stroke and exhibit an increased infarct volume that disrupts BBB tight junctions (Hom et al., 2007). As a result, immunodepression in hypertensive patients with stroke is even more severe. Diabetes is another risk factor for stroke, and stroke patients with diabetes present with a greater number of adverse events and higher mortality. The number of people who suffer from diabetes is estimated increase to 439 million worldwide by 2030 (Chen et al., 2016). Hyperglycaemia is a common phenomenon observed in the early stage of acute stroke. Studies have shown an increased risk of pneumonia in patients with diabetes and stroke (Liao et al., 2015), and the postulated mechanisms underlying the impact of diabetes on SAP are listed below. (1) Patients with diabetes are generally immunocompromised and their neutrophil function is lower than the normal population (Dryden et al., 2015). (2) The occurrence of diabetes is often accompanied by pathological changes in the structure and function of the blood vessels, leading to abnormal blood flow and circulatory arrest, as well as stroke. In patients with diabetes, cerebral vessels directly affect and aggravate the conditions of ischemia and hypoxia (Chen et al., 2016). (3) The glucose level at admission and a history of diabetes mellitus are correlated with poor clinical outcomes after thrombolysis. An initial high plasma glucose level increases BBB disruption and lactic acid production in ischemic tissues, thus causing a greater final infarct size after stroke and increasing the likelihood of immunodepression and susceptibility to infection (Chen et al., 2016, Desilles et al., 2013). (4) Hyperglycaemia is a suitable condition for bacterial production and reproduction; therefore, the combination of stroke and diabetes may increase the risk of pulmonary infection (Gill et al., 2016). (5) High blood glucose levels may deteriorate the pulmonary microcirculation by reducing the phagocytic function of leukocytes and oxygen-carrying capacity of erythrocytes, resulting in greater vulnerability to pulmonary infections (Sui and Zhang, 2011).

In addition to the factors mentioned above, other modifiable and unmodifiable factors may also affect the occurrence of SAP. For example, an acute insular lesion has a specific role in the pathogenesis of stroke-induced sympathetic hyper-activation and immunodepression (Walter et al., 2013). In addition, an ischemic lesion in the anterior middle cerebral artery (MCA) in the cortex may be also a major determinant of SAI (Harms et al., 2011). The infarct volume clearly plays an important role in the occurrence of SAP, and lesions in specific brain locations are also associated with an increased risk of pneumonia (Urra et al., 2017). The potent androgen dihydrotestosterone (DHT) has been shown to exacerbate post-ischemic peripheral immunodepression (Dziennis et al., 2011). Compared with males, females are less likely to be infected with pneumonia after stroke, which may be related to sex hormones (Colbert et al., 2016). Taking one with another, patients with the following characteristics are more susceptible to infections: older age, males, bilateral lesions, severe neurological deficits (Maeshima et al., 2014), alcohol consumption, atrial fibrillation (Matz et al., 2016), nasal feeding, a lower consciousness level (Ashour et al., 2016), hemispheric stroke and more. Many different scoring systems are used to predict SAP. For example, the Preventive Antibiotic in Stroke Study (PASS) is used to assess whether preventive antibiotic treatments improve functional outcomes at 3 months by preventing infections (Westendorp et al., 2014). The PANTHERIS score might be a useful predictive tool to early identify stroke patients at a high risk of SAP (Harms et al., 2013). Scales such as the Glasgow Coma Scale (GCS) and National Institutes of Health Stroke Scale (NIHSS) are used to evaluate the functional state of patients, and they have reference value for defining prognoses (Sahan et al., 2013). How to make better use of these scoring systems to assess stroke patients is also a difficult problem for clinical practice.

The immune system is composed of immune organs, immune cells and immune active substances, and is the most effective weapon to prevent pathogen invasion. A regulatory network comprising the immune system, the nervous system and the endocrine system has been suggested to coordinate the functions of various systems and organs (Procaccini et al., 2014). The nervous system is divided into two parts: the CNS and the peripheral nervous system. The CNS includes the brain and spinal cord, and the peripheral nervous system includes the cranial nerve, the spinal nerve and the autonomic nerve. The autonomic nerve, which is also known as visceral nerve, is divided into the sympathetic nerve and parasympathetic nerve. Through the HPA axis and the autonomic nervous system (ANS), the CNS releases various inhibitory cytokines, hormones, neurotransmitters, neuropeptides and other soluble molecules (Procaccini et al., 2014). In this way, the CNS accurately regulates the body's immune responses to achieve the purposes of neutralizing invasive pathogens, repairing damaged tissues and regulating pathogen responses in host tissues. As the centre of the endocrine system and the nervous system, the hypothalamus regulates the visceral and endocrine activities and is also an important centre of immune regulation in the CNS. As shown in Fig. 2, at least two pathways regulate the immune function of the CNS after stroke, the humoral pathway and the neural pathway (Dantzer and Wollman, 2003), which include the HPA axis, the vagus nerve, and the SNS.

The humoral pathway is a regulatory mechanism based on changes in humoral immunity in the body, including neurotransmitters, neuropeptides, hormones and other chemical substances. Inflammation occurs a few minutes after the onset of cerebral ischemia. Some cytokines, such as interleukin (IL)-1, TNF-α and IL-6, are secreted by cells in different tissues and organs to stimulate specialized neurons in the paraventricular nucleus (PVN) of the hypothalamus that synthesize corticotropin-releasing factor (CRF) in response to stress (Chamorro et al., 2007, Esmaeili et al., 2012). CRF acts on both the brain and periphery to coordinate the overall response of the body to stress. CRF induces the dilation of cerebral blood vessels and increases cerebral blood flow (CBF) after stroke, and CRF receptor antagonists reduce ischemic damage in rats (De Michele et al., 2007). CRF is secreted into the pituitary portal blood system and facilitates the secretion of adrenocorticotropin hormone (ACTH), which is related to the secretion of glucocorticoids. As mentioned earlier, glucocorticoids are mainly responsible for lymphocytopenia post-stroke (Mracsko et al., 2014a).

The neural pathway directly activates or inhibits the immune regulation centre through the transmission of nerve signals, mainly by regulating the sympathetic nerve in the immune system. In recent years, sympathetic nerve fibres were also shown to be distributed in all primary (bone marrow and thymus) and secondary immune organs (spleen and lymph nodes) and released catecholamine from efferent nerves to modulate immune functions (Bellinger et al., 2008). Elevated levels of CRF in the ventricles of the brain enhance sympathetic discharge, increasing the levels of catecholamine neurotransmitters. The rapid increase in the amount of catecholamine increases the number of granulocytes and lymphocytes in the blood. However, a persistent increase in catecholamine levels potentially reduces the number of circulating lymphocytes, resulting in immune organ atrophy, decreased immunity and an increased risk of infection (Prass et al., 2003, Vogelgesang et al., 2014). In addition, stroke activates pro-inflammatory pathways in the liver, causes hepatic insulin resistance and eventually leads to hyperglycaemia in the absence of diabetes, which is also related to excessively increased catecholamine levels (Wang et al., 2014).

Regardless of whether nerve conduction or fluid conduction is involved, changes in the function of the immune system eventually occur after stroke.

As reflected in Table 1, some potential treatment directions for SAP have been identified.

Controversy exists in whether early prophylactic use of antibiotics reduces the incidence of infection in patients with acute severe stroke. Prophylactic antibiotic therapy has been shown to reduce mortality after stroke and Phase III trials are warranted to prove this concept to clinical setting (Hetze et al., 2013). However, another meta-analysis by Van de Beek and colleagues showed that preventive antibiotics reduced the risk of infection, but did not reduce mortality in adults with acute stroke (van de Beek et al., 2009). Nevertheless, an article has also questioned the rigor of the study by Van de Beek and colleagues (Schwarz, 2010). In a mouse model of stroke, preventive antibacterial therapy with moxifloxacin not only prevented the development of infections and fever but also reduced mortality and significantly improved neurological outcome (Meisel, 2003). Next, the authors investigated whether this approach was effective in stroke patients. According to the PANTHERIS study, although the infection rate was reduced in patients treated with moxifloxacin, survival and neurological outcomes were not significantly improved compared to placebo (Harms et al., 2008). Recent results from clinical trials show that preventive antibiotic treatments may not be recommended for patients with acute stroke because they do not reduce the rate of SAP or mortality, even though the risk of infections, particularly urinary tract infections, decreases (Kalra et al., 2015, Liu et al., 2016, Westendorp et al., 2015). The treatment of all stroke patients with a broad-spectrum antibiotic is an unreasonable solution to reduce the risk of post-stroke infections, and the potential promotion of bacterial resistance must be considered (Meisel, 2015). Various kinds of antibiotics may play different roles in different stages of stroke. Very early treatment, either prophylactically or in response to an established infection, with certain classes of antibiotics (i.e., fluoroquinolones) after stroke onset is detrimental in improving outcomes in rodents. The negative impact of enrofloxacin on the early stage of stroke was attenuated by delaying antibiotic therapy (Becker et al., 2016). Based on these data, a large clinical trial is warranted, although most studies suggest that prophylactic antibiotics should not be used to treat acute pneumonia in stroke patients, and verified biomarkers or clinical scores that identify patients at high risk for post-stroke infections must be selected before antibiotics are administered.

SIDS may represent an adaptive mechanism to limit tissue damage and prevent detrimental autoreactive immune responses after stroke. Dual blockade of the SNS with the β-receptor blocker (BB) propranolol and the HPA axis with the glucocorticoid receptor antagonist mifepristone significantly reduces the infarct volume, improves long-term survival and promotes recovery from infections of mice with stroke. The inhibition of SIDS by blocking the SNS and HPA axis increases autoreactive CNS antigen-specific T-cell responses in the brain but does not worsen long-term functional outcomes after experimental stroke (Romer et al., 2015). BB is mainly competitive with catecholamine for binding to β-receptors, thereby blocking the excitatory effects of catecholamine. In a large nonrandomized comparative study, BB was associated with reduced mortality on-stroke and the incidence of nosocomial pneumonia pre-stroke and on-stroke (Sykora et al., 2015). The use of BB propranolol partially reverses the reduction in spleen volume after stroke (Yan and Zhang, 2014). An intraperitoneal injection of 6-hydroxydopamine HBr (6-OHDA) inhibits SNS activity, subsequently diminishing NF-κB activation and enhancing β-arrestin2 expression. SNS inhibition does not worsen the functional outcomes of stroke patients, and thus it may be a viable treatment for stroke (Deng et al., 2016). However, based on the results of another clinical study, BB therapy significantly reduces the risk of urinary tract infections but not SAP (Maier et al., 2015). Westendorp et al. verified that patients included in the PASS who were treated with BB prior to stroke have a higher rate of infections and pneumonia, but not urinary tract infections (Westendorp et al., 2016). This controversial result may be related to a variety of factors. For example, patients on BB were older and the majority had comorbidities and used more medications than patients who were not taking BB. The role of the cholinergic anti-inflammatory pathway has been discussed above.

New uses for conventional drugs, such as statins, are increasingly recognized due to their confirmed safety. Statins exert neuroprotective effects, limit damage, improve recovery and prevent the early recurrence of stroke; thus, statins have been claimed to exert potential positive effects on the acute phase of ischemic stroke (Chen et al., 2014). Moreover, by attenuating spleen atrophy and lung bacterial infection, simvastatin has been shown to ameliorate SIDS (Jin et al., 2013). A meta-analysis confirmed the importance of statins in the treatment of cerebral ischemia and noted that simvastatin exerts the strongest neuroprotective effect on brain injury (Garcia-Bonilla et al., 2012).

Hypothermia therapy has increasingly gained acceptance as a treatment for stroke or hypoxic-ischemic encephalopathy in new-borns. Hypothermia robustly attenuates the volume of the cerebral infarction, and brief intra-ischemic hypothermia (28–30 °C, 1 h) improves the immune suppression state by reducing the infarct volume (Gu et al., 2014). However, some studies have confirmed that hypothermia plays a neuroprotective role in ischemic brain regions, aggravates immunodepression and increases the susceptibility to infectious complications by inhibiting the cytokine response and stimulating anti-inflammatory cytokine release from T-cells (Lee et al., 2001). Researchers have disputed whether hypothermia is a beneficial treatment for SAP, because the time window for initiating hypothermia, the duration and depth of hypothermia, the use of intermittent or continuous hypothermia, the use of whole body cooling or selective head cooling, the rewarming speed and the selected temperature all influence the immune state (Han et al., 2015, Polderman and Herold, 2009). Clinical applications of physically induced hypothermia are hindered due to its inefficiency and impracticality. Eight classes of pharmacologically induced hypothermia drugs used in stroke models are listed in Table 1 (Zhang et al., 2013). Large-scale studies examining the effects of hypothermia on stroke are needed before hypothermia treatment is implemented at a clinical level, and an optimal balance between the beneficial and adverse effects of hypothermia must be achieved.

In recent years, stem cell-based gene therapy has attracted more attention in stroke due to its neuroprotective effects and ability to induce neuronal repair (Hao et al., 2014). Bone marrow mesenchymal stem cell (BMSC), an important member of the stem cell family, is one of the hot spots in the field of stem cell research. In recent years, BMSCs have achieved great progress in the treatment of ischemic stroke (Li et al., 2016). BMSCs function in immune regulation and immune reconstitution, and thus may be a good research direction for SAP. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) were recently reported to be an important material for cellular communication, and they are well-tolerated in humans and accelerate neural functional recovery (Hu et al., 2016). Therefore, the administration of EVs in clinical settings might establish a novel and innovative therapeutic direction for treating stroke with fewer side effects (Doeppner et al., 2015, Koniusz et al., 2016). Generally, stem cells are derived from various sources, and animal studies have utilized various methods of cell delivery or implantation (Misra et al., 2012). Many hurdles of current stem cell therapy in stroke treatment must be overcome, such as the optimal time window, inherent limitations of stem cells and possible adverse effects of transplanted cells, among others (Bang et al., 2016).

Increasing evidence shows that targeting inflammation and immune responses may be a viable approach to rescuing brain tissue and improving outcomes after stroke. Some drugs that specifically modulate inflammatory or immune pathways have reached Phase II or Phase III clinical trials for acute stroke, such as the IL-1 receptor antagonist (Anakinra), Statins, Fingolimod (FTY720), Citalopram, Donepezil, Cyclosporine A, uric acid, Natalizumab, Ginsenoside-Rd, and Edaravone (MCI-186) (Smith et al., 2015). In addition, the novel non-toxic caspase inhibitor Q-VD-OPH ameliorates brain damage, enhances antibacterial defences, and reduces spontaneous bacterial infections following experimental stroke (Braun et al., 2007). Next, we will describe the post-stroke functions of the immune system and current hotpots in immune system research.

Bone marrow is the place where all kinds of blood cells and immune cells are produced and mature. As a type of immune cells, B cells mainly develop and mature in the bone marrow. The thymus is the main lymphoid organ of the human body, and it is the site for T cell differentiation, development and maturation. In addition, the thymus regulates peripheral immune organs and immune cells. SIDS has an important effect on the thymus, as it causes programmed cell death (Braun et al., 2007). Thymosins are a group of physiologically active polypeptides secreted by the thymus that regulate and enhance human immune cell function. By decreasing the level of inflammatory factors, enhancing cellular immunity and humoral immunity, Thymosin α1 balances the immune system, and thus it represents a potentially effective strategy for preventing and treating pulmonary infections in critically ill patients who received a tracheotomy (Huang et al., 2006).

Changes in the spleen after stroke have been studied more extensively than changes in other peripheral immune. The spleen is the largest peripheral lymphoid organ in humans and has functions in haematopoiesis, filtering blood, removing senescent blood cells and participating in the immune response. In the early stage of brain injury, the CNS signals to the α- and β-adrenergic receptors in the spleen through the catecholamines secreted by the SNS (Yan and Zhang, 2014), causing apoptosis of spleen host cells and spleen atrophy (Offner et al., 2006b). According to clinical studies, spleen atrophy also occurs in the acute phase of ischemic stroke in humans, and changes in spleen volume may be associated with the post-cerebral ischemia inflammatory cascade; therefore, sustained contraction may be a marker of poor clinical outcomes (Sahota et al., 2013). During the acute phase of stroke, multiple splenic cells such as monocytes/macrophages migrate into the brain and aggravate inflammation. As shown in an animal experiment, a splenectomy reduced the number of monocytes/macrophages that infiltrate into the cerebral cortex, but did not reduce infarct volume (Kim et al., 2014). However, removal of the rat spleen two weeks prior to MCAO reduced the infarct volume (Pennypacker and Offner, 2015). A latest research showed that splenectomy two weeks before stroke or immediately after reperfusion also resulted in improved neurobehavioral and infarct outcomes in aged male mice (Chauhan et al., 2017). According to current studies, the selection of animal strains (C57BL/6 mice, Lewis rats, Sprague-Dawley rats), animal sex (Dotson et al., 2015), type of stroke (transient focal ischemic, permanent focal ischemic, hypoxic/ischemic injury), and time of splenectomy (immediately before stroke, 2 weeks/3 days before stroke, immediately after reperfusion) all influence the post-stroke infarct volume (Zierath et al., 2017). Therefore, a stable and reliable stroke model must be established to study the changes in immune organs after stroke.

Immune cells are commonly known as white blood cells or leukocytes and comprise lymphocytes (T cells, B cells, NK cells and NKT cells), phagocytes, mast cells, and platelets. White blood cell counts are used as a reference index for monitoring and determining the prognosis of patients with acute stroke. In stroke patients with elevated white blood cell counts, the severity of stroke, the degree of disability at discharge and the 30-day mortality post-stroke were higher (Furlan et al., 2014). Neutrophils are the first activated immune cells to reach the site of inflammation after stroke, followed by monocytes, macrophages, T cells and dendritic cells. Another review has described the role of neutrophils in stroke (Strecker et al., 2017). Next, we focus on the changes in lymphocytes after stroke.

A reduction in overall T cell subpopulations, rather than B cells, was associated with the risk of SAI (Urra et al., 2009). A remarkable and immediate loss of T-lymphocytes was observed as early as 12 h after stroke onset (Vogelgesang et al., 2008). T cells are the main immune cells that mediate the cellular immune response, and strategies targeting T cell migration may be a promising therapeutic approach for stroke (Liesz et al., 2011). According to their different functions in the immune response, T cells are divided into several recognized subsets: helper T cells (Th), regulatory T cells (Treg) and cytotoxic T cells (Tc). Earlier models of Th cell differentiation focused on Th1 cells and Th2 cells. According to the signature cytokine secreted by each subset after activation, three additional Th cell subtypes have been discovered and designated as Th17, Th9, and Th22 cells (Th-17: IL-17, Th9: IL-9, and Th22: IL-22) (Schmitt et al., 2014). Th1 cells play an important role in protecting the organism against intracellular pathogen infection, and the main function of Th2 cells is to stimulate the proliferation of B cells and the production of immunoglobulin G (IgG) 1 and IgE antibody, which is associated with humoral immunity. Either an enhancement of the Th2 response or prevention of the Th1 and Th17 responses exerts a neuroprotective effect following stroke (Luo et al., 2015). SAP is associated with an increase in Th1 but not Th17 responses to myelin basic protein (MBP) after stroke (Becker et al., 2016). In addition, Th cells are also known as CD4+ cells and Tc cells are known as CD8+ cells. Different subtypes of T cells play different roles in brain injury after stroke, and Th (CD4+) cells or Tc (CD8+) cells increase the volume of cerebral infarction and increase the nervous system damage after cerebral ischemia (Liesz et al., 2011, Yilmaz et al., 2006). However, another study verified that CD4+ cell dysfunction contributes to immunosuppression in stroke (Vogelgesang et al., 2008). FoxP3+CD25+CD4+ Treg-mediated immunodepression is either protective or harmful at different stages of stroke; controversy still exists regarding whether Treg cells are targeted for immune regulation (Chen et al., 2013, Liesz et al., 2015). T cells have various functions in various stages of stroke (Gill and Veltkamp, 2016); therefore, strategies targeting T cells may represent a promising therapeutic approach for ischemic stroke, and the key of which is to prevent the activation and extravasation of circulating immune cells to reduce infection. However, researchers have not clearly determined whether T cells can be used as a target to improve the status of SIDS, and further studies on the relationship between T cells and stroke are needed. In addition, sex and age factors also have important implications for T cell alterations. Hormone levels and complications change throughout the lifespan, and T cell responses also changed accordingly (Bravo-Alegria et al., 2017). Severe combined immunodeficient (SCID) mice, which lack T and B cells, are commonly used in studies of immune cell differentiation, immunodeficiency diseases, oncology and other aspects. Researchers have established the MCAO model in SCID mice and verified that T and B lymphocytes are highly injurious factors in early ischemic brain injury. In addition, T cell populations had no impact on the core damage, but rather influenced the penumbra (Hurn et al., 2007).

B cells can differentiate into plasma cells following antigen stimulation, and plasma cells can synthesize and secrete antibodies (immunoglobulins). B cells are the main immune cells that mediate the humoral immune response by producing antibodies. The decrease in the number of B cells is particularly pronounced in stroke patients at admission, whereas low levels of circulating B cells are correlated with poor outcomes at follow-up (Urra et al., 2009). Splenic marginal zone (MZ) B cells are major sources of IgM, particularly during the early stage of infection. Splenic MZ B cells are innate-like lymphocytes that provide early defence against bacterial infections. Experimental stroke in mice induces a marked loss of MZ B cells, deficiencies in capturing blood-borne antigens and the suppression of circulating IgM levels. β-adrenergic receptor antagonism after experimental stroke prevents the loss of splenic MZ B cells, preserves IgM levels, and reduces the bacterial burden. Adrenergic-mediated loss of MZ B cells contributes to the infection-prone state after stroke and identifies systemic B-cell disruption as a target for therapeutic manipulation (McCulloch et al., 2017).

High circulating NK cell counts within the first hours after ischemic stroke onset followed by a decrease in the numbers of all lymphocyte subsets may be helpful in identifying patients who are susceptible to infections (De Raedt et al., 2015). NK cells rapidly produce large amounts of cytokines, mainly IFN-γ. NK cells negatively affect the BBB during stroke and promote neural cell necrosis via IFN-γ (Zhang et al., 2014). Activated invariant natural killer T (iNKT) cells release copious amounts of pro-inflammatory cytokines, such as TNF-α and IFN-γ, in a short time. The glycolipid ligand α-galactosylceramide (α-GC) is known as a potent iNKT cell agonist. iNKT cells stimulated with α-GC are responsible for a wide array of immune responses with many promising immunotherapeutic applications, including the enhancement of vaccine efficacy against infectious diseases and cancer (Artiaga et al., 2016). Stroke-induced activation of iNKT cells mediates an immunodepressive response, and the magnitude of this response is closely associated with the severity of stroke injury and renders the patients more susceptible to infection (Wong et al., 2017). Within 48 h of focal permanent cerebral ischemia in mice, iNKT cells infiltrate into the brain and contribute to brain infarction. An α-GC treatment further increases the number and infiltration of iNKT cells for up to 48 h (Wang et al., 2016).

Immune active substances mainly include complement, lysozymes, immunoglobulins, and cytokines. New research show that partial major histocompatibility complex (MHC) class II molecules pMHC, also known as Recombinant T-cell receptor ligands (RTL), are capable of treating various models of ischemic stroke in mice by reducing infarct volume and neurological deficit, reversing splenic atrophy and promoting a protective M2 macrophage/microglia phenotype in the CNS (Benedek et al., 2017). Partial MHC class II constructs may be novel immunomodulatory therapy for stroke, and related clinical research needs to be expanded. Next, we mainly focus on cytokines because they are most closely correlated with stroke. Communication between the neuro-endocrine system and the immune system mainly depends on the chemical messenger, and the cytokines released by the immune system play a major role in the interaction with the CNS (Procaccini et al., 2014). Cytokines are divided into the IL family, IFN family, tumour necrosis factor superfamily (TNF), colony-stimulating factor (CSF), transforming growth factor-β (TGF-β) family, chemokine family, and growth factors (GF). Inflammatory cytokines, chemokines, and chemokine receptors (CCR) are dynamically activated throughout the peripheral immune system after stroke (Offner et al., 2006a). Cytokines contribute to the progression of ischemic cerebral damage because they play an important role in the inflammatory mechanism of stroke (Doll et al., 2014).

Many cytokines exacerbate secondary brain injury in the early stage of stroke, but they also beneficially contribute to brain recovery in the late stage. Pro-inflammatory cytokines, such as TNF-α, IL-1, IL-6 and IL-8, which are in part produced by microglia, are potential targets for future stroke therapy because they aggravate the damage of brain tissues in experimental stroke models (Lambertsen et al., 2012). However, other researchers used IL-6 knockout (IL-6−/−) mice and confirmed that IL-6 produced locally by resident brain cells promoted angiogenesis after stroke, highlighting the importance of neuroinflammation for chronic post-stroke recovery (Gertz et al., 2012). Anti-inflammatory cytokines such as IL-4 and IL-10 may have a protective effect on the brain. Pro-inflammatory and anti-inflammatory cytokines are not balanced after stroke, and this imbalance can affect functional outcomes. The use of one cytokine as a potential biomarker or a therapeutic target is infeasible in patients with stroke; thus further clinical and experimental studies are warranted to better balance the cytokines (Doll et al., 2014).

Inflammation is a hallmark of stroke pathology. In addition to the conventionally researched cytokines, such as IL-1, IL-6 and TNF-α, many other pro-inflammatory and anti-inflammatory cytokines are beginning to be studied in stroke.

  • (1)

    IFN-γ is an important effector cytokine produced by NK and T cells that acts as a key regulator of immune and inflammatory responses. Reduced IFN-γ production induced by impaired NK and T cell responses is one of the critical stroke-induced defects in the antibacterial defence mechanism. Researchers verified that early (24 h) but not late (48 h) administration of recombinant IFN-γ substantially reduced the blood and pulmonary bacterial burden, suggesting that the rapid production of IFN-γ by lymphocytes is required to control bacterial infections (Prass et al., 2003). IFN-γ represents a potential early diagnostic marker and a new therapeutic target for patients with SAI (Lin et al., 2016). The role of IFN-γ in brain injury has been controversial. IFN-γ may be one of the inflammatory signals originating from the spleen that aggravates the delayed inflammatory response post-stroke, and blockade of splenic IFN-γ maybe a therapeutic strategy to modulate the immune response following stroke. A splenectomy reduces IFN-γ expression in the brain after stroke, and the systemic administration of IFN-γ reverses the protective effects of a splenectomy (Seifert et al., 2012).

  • (2)

    IL is a class of at least 38 different cytokines known as IL-1 to IL-38 that are produced by a variety of cells. IL-33 is a novel member of the IL-1 cytokine family and is known to induce the production of anti-inflammatory cytokines. IL-33 protects against ischemic insult by inducing IL-4 secretion in the spleen and the peri-ischemic area of the cortex (Korhonen et al., 2015), modulating T cell subsets (promoting Th2 responses and suppressing Th17 responses) in the brain, and altering the serum IFN-γ, IL-4 and IL-17 levels (Luo et al., 2015). The IL-23/IL-17 axis induces inflammation and aggravates immune injury in the pathophysiological process of cerebral infarction in mice (Ma et al., 2013). IL-23 is primarily produced by infiltrated macrophages and its levels increase on day 1 after stroke, suggesting that this cytokine functions in the acute stage. However, IL-17 levels are elevated after day 3, and IL-23 is a key factor that induces IL-17 expression. Therefore, IL-17 has an important role in the delayed phase of cerebral injury (Shichita et al., 2009). RNA interference-mediated knockdown of IL-23p19 efficiently suppresses the IL-23/IL-17 axis, improves the outcomes of the later stage of cerebral ischemia and reduces the infarct volume (Zheng et al., 2015). Therefore, immunomodulatory strategies that regulate the expression of the IL-23/IL-17 axis are promising targets for stroke and SAP.

  • (3)

    Chemokine-like factor 1 (CKLF1) is a new kind of chemokine that plays important roles in immune-related diseases. Based on preliminary studies, CKLF1 may be a novel target for the treatment of stroke because it is associated with neuronal apoptosis after stroke (Kong et al., 2014). In addition, the expression of CKLF1 increases after focal cerebral ischemia, and inhibition of CKLF1 using the C19 peptide antagonist or anti-CKLF1 antibody protects against cerebral ischemia (Kong et al., 2012). As an antagonist of CKLF1, a new coumarin compound, IMM-H004, was recently shown to be an effective treatment for cerebral ischemic (Li et al., 2010, Niu et al., 2017). More experiments are needed to verify whether IMM-H004 is an efficient treatment for SAP.

Concerns exist that immunotherapy in patients with stroke may exacerbate SIDS and increase infectious. Another review details the current clinical advances in immunotherapies targeting E-selectin, Nogo-A, and intercellular adhesion molecule-1 (ICAM-1, also known as CD54), among other molecules in stroke (Yu et al., 2013).Immunotherapy has not been widely used in stroke due to many uncertainties. Some researchers have recommended the restricted usage of immunotherapy. (1) The greatest challenge facing preclinical research in ischemic stroke is the difficulty in translating scientific advances into clinical practice (Peng et al., 2017). Some immunotherapies have been verified to exert a protective effect on stroke in animal models, but animal experiments do not fully mimic the clinical situation of patients. In the clinic, stroke patients are often complicated with other basic diseases and are older in age. However, when selecting experimental animals, researchers usually choose young animals that do not present other complications. In addition, many drugs used in animal experiments are administered intracerebroventricularly, which is not feasible in the clinic. Animal experiments include too many uncertain factors; therefore, findings must be confirmed in an animal model that more precisely mimics the clinical disease. (2) The mechanism of the interaction between the CNS and the immune system after stroke has not been fully elucidated, and the immunodepression observed in different stages of stroke has different effects. Immune and inflammatory responses after stroke are a double-edged sword (McCombe and Read, 2008). (3) The diagnosis of SAP poses particular challenges due to the considerable variation in terminology and the diagnostic approaches for SAP (Kishore et al., 2015). In the early stage of stroke, the common diagnostic features of pneumonia, such as pyrexia, cough and purulent sputum, are not manifested. In addition, the conventional methods for detecting pneumonia are not useful in the early detection of SAP. Therefore, specific biomarkers must be selected to predict the risk of SAP and for the early implementation of interventions. For example, elevated C reactive protein levels are closely related to the occurrence of SAP (Gándara et al., 2016). The predictive value of appropriate diagnostic markers must be validated in prospective clinical trials with a large population.

Section snippets

Conclusions

Recent research clearly confirms that the normally well-balanced interplay between the immune system and the CNS is disturbed by CNS injury and significantly increases patients’ susceptibility to infections (Chamorro et al., 2012, Meisel et al., 2005). Strategies used to prevent and treat cerebrovascular diseases have the characteristics of long-term medication and multi-drug combinations. Research and development of pharmacogenomics and individualized treatments are urgently to provide new

Acknowledgement

This work was supported by the National Natural Science Foundation of China (81730096, U1402221, 81603315, 81560685), CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-004), Key Research and Development Projects of ShanDong (2016ZDJS07A21), Program for Changjiang Scholars and Innovative Research Team in University (No. IRT_14R41), PUMC Graduate Education and Teaching Reform Project (10023201600801), Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study (

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