Stroke-induced immunosuppression: implications for the prevention and prediction of post-stroke infections

Abstract

Stroke produces a powerful inflammatory cascade in the brain, but also a suppression of the peripheral immune system, which is also called stroke-induced immunosuppression (SIIS). The main processes that lead to SIIS are a shift from a lymphocyte phenotype T-helper (Th) 1 to a Th2 phenotype, a decrease of the lymphocyte counts and NK cells in the blood and spleen, and an impairment of the defense mechanisms of neutrophils and monocytes. The direct clinical consequence of SIIS in stroke patients is an increased susceptibility to stroke-associated infections, which is enhanced by clinical factors like dysphagia. Among these infections, stroke-associated pneumonia (SAP) is the one that accounts for the highest impact on stroke outcome, so research is focused on its early diagnosis and prevention. Biomarkers indicating modifications in SIIS pathways could have an important role in the early prediction of SAP, but currently, there are no individual biomarkers or panels of biomarkers that are accurate enough to be translated to clinical practice. Similarly, there is still no efficient therapy to prevent the onset of SAP, and clinical trials testing prophylactic antibiotic treatment and β-blockers have failed. However, local immunomodulation could open up a new research opportunity to find a preventive therapy for SAP. Recent studies have focused on the pulmonary immune changes that could be caused by stroke similarly to other acquired brain injuries. Some of the traits observed in animal models of stroke include lung edema and inflammation, as well as inflammation of the bronchoalveolar lavage fluid.

The Relationship Between Serum YKL-40 Levels on Admission and Stroke-Associated Pneumonia in Patients with Acute Ischemic Stroke

“… 29 , 30 Thirdly, some studies have shown the association of immunosuppression and other unstable conditions such as renal failure, hepatic failure and cancer with SAP. 31 , 32 However, these factors were not measured in our study protocol, and we did not exclude the effects of these factors on SAP. Also, we cannot totally exclude the underlying effect of other undetected conditions such as stress biomarkers, genetic predisposition on YKL-40 and COVID-19 status.…”

SNHG15 is a negative regulator of inflammation by mediating TRAF2 ubiquitination in stroke-induced immunosuppression

“…Accumulating evidence indicates that lncRNAs are involved in central and peripheral immune systems after stroke [ 22 , 23 ]. Stroke induces repression of the peripheral immune system, which contributes to the incidence of post-stroke infections [ 11 ]. In this study, we investigated lncRNA expression profiles in monocytes/macrophages after stroke and identified an lncRNA with stroke-induced upregulation (SNHG15).…”

“…SIIS is characterized by an imbalance in the systemic cellular immune response, including dysfunction of monocytes and a rapid decrease in peripheral lymphocyte subpopulations, both of which increase the risk of SAI [ 10 ]. Furthermore, SIIS is an independent predictor for SAI, suggesting that immuno-inflammatory response plays an important role after stroke [ 6 , 11 ]. Our previous study found that the sympathetic pathway is enhanced after ischemic stroke and subsequently induces significant changes in the levels of cytokines in the periphery [ 9 ].…”

The “Dialogue” Between Central and Peripheral Immunity After Ischemic Stroke: Focus on Spleen

“…This immunosuppressed state is known as stroke-induced immune depression syndrome (SIDS) ( 18 ). The main processes leading to immunosuppression is related to the change from the lymphocyte phenotype T-helper Th1 to Th2 phenotype, a decrease in lymphocyte and NK cells counts in the blood and spleen, and impaired defense mechanisms of neutrophils and monocytes ( 19 ). This process is associated with the activation of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system (SNS), with increased secretion of adrenocorticotropic hormones and catecholamines, which exerts immunosuppressive effects ( 20 ).…”

“…Catecholamines such as epinephrine and norepinephrine are mediators of the SNS and are secreted when the SNS is activated. They inhibit Th1-lymphocyte activity and cellular immune responses through processes such as β-adrenergic receptor action of immune cells, and inhibition of IFN-γ production with stimulation of IL-10 production by immune cells ( 19 ).…”