Stroke is the second leading cause of death in the Western world after heart disease (Donnan et al. 2008). The medical condition is characterized by the rapid death of brain cells in a localized area due to inadequate supply of oxygen. There are two types of strokes: ischemic (lack of blood flow) and hemorrhagic (leakage of blood). Increased susceptibility to infection is the major cause of death that results from stroke (Kimura et al. 2005; Langhorne et al. 2000). The main mechanism behind the increased susceptibility seen in post-stroke patients is immunosuppression. If you think about this situation from the brain’s perspective, it makes a lot of sense for the body to promote immunosuppression after an ischemic attack because this protects the post-ischemic brain from tremendous inflammation. However, there is always a catch. Although the brain is protected from inflammation, post-stroke immunosuppression leaves the body prone to infection. The mechanism behind the observed immunosuppression is not well established. However, a recent study by Wong et al. (2011) reveal the role of invariant NKT (iNKT) cells in the immunosuppression process. NKT cells are a type of T cell that shares characteristics with both T cells and natural killer cells. NKT cells express both an αβ T cell receptor and molecules associated with NK cells. iNKT cells are so called invariant because they possess the invariant T cell receptor α chain. Many iNKT cells recognize the CD1d molecule, which binds self and foreign lipid antigens. iNKT cells are also primarily located in the liver and the spleen
In the study, Wong et al. used a rodent model of stroke called midcerebral artery occlusion (MCAO) in order to mimic the condition of stroke. Normally, iNKT cells move through the hepatic blood vessels. However, when they are activated by CD1d ligands, their movement is restricted. Using intravital spinning disk confocal microscopy, a technique that allows researchers to study living blood vessels in the context of inflammation and coagulation, the authors examined the movement of the iNKT cells both before and after inducing stroke in the animals. They found that after stroke, there was a significant reduction in the movements of iNKT cells and an increase in the number of stationary iNKT cells. These results suggest that brain injury is capable of changing the movement behavior of iNKT cells.
The authors then wanted to determine whether the immunosuppression seen in stroke patients was a result of a shift from a Th1 response (pro-inflammatory) to a Th2 response (anti-inflammatory). After the induction of stroke, the authors found a decrease in the levels of Th1 cytokines such as IFN-γ but an increase in the levels of Th2 cytokines such as IL-10 and IL-5. In accordance with this finding, there was an observed increase in infection rate that was detected in the blood, lung, liver, and spleen after induction of stroke. In order to further investigate the role of iNKT cells in immunosuppression, the authors subjected mice that are genetically deficient in iNKT cells to stroke. Results reveal that these mice had an even greater pulmonary damage after stroke induction. In addition, there was an increased mortality rate in these mice due to the increased susceptibility to infection post-stroke. Treatment with antibiotics increased the survival rate in both the iNKT-deficient mice and the wild-type mice after stroke induction. Furthermore, when the wild-type mice were treated with IL-10, an anti-inflammatory Th2 cytokine, there was an increased development of lung infections in these mice after stroke induction.
As stated earlier, iNKT cells recognize CD1d molecules that present lipid antigens. In order to determine whether CD1d is responsible for the immune effects of iNKT cells, the authors blocked CD1d with an antibody. However, this blockade did not have any effect on the stationary state of the iNKT cells after stroke induction. Previous studies have implicated the role of the nervous system in modulating the immune response. Therefore, the authors wanted to test whether a nonspecific β-adrenergic receptor blocker, called propranolol, would have any effect on the state of iNKT cells after stroke. Results show that nonspecific blockage of β-adrenergic receptors failed to induce the iNKT phenotype normally induced by stroke. In accordance with this finding, mortality was completely inhibited by propranolol administration.
iNKT cells in vitro were treated with noradrenaline, a neurotransmitter that binds to noradrenergic receptors. Treatment with noradrenaline caused the iNKT cells to adopt a “flattened” phenotype, similar to what was seen in iNKT phenotype after stroke induction in vivo. These results suggest that noradrenaline induces the iNKT phenotype observed in vivo. Unexpectedly, when the authors administered another iNKT cell activator called α-galactoceramide (α-GalCer), this not only increased IFN-γ levels, a pro-inflammatory Th1 cytokine, but also decreased infections in post-ischemic mice. These results suggest that immunosuppression is not mediated by iNKT cell activation per se, but rather, immunosuppression is mediated by the regulatory role of noradrenaline in shifting the immune response from a Th1 pro-inflammatory response to a Th2 anti-inflammatory response. On the other hand, blocking β-adrenergic receptors with propranolol reversed the immune response from a Th2 to a Th1 response, driven primarily by IFN-γ production. All these findings suggest that iNKT cells are directly modulated by α-GalCer administration and noradrenergic receptor blockade. Furthermore, these two modulators are sufficient to decrease infection and lung injury that are normally seen after stroke.
The results of the study provide further insight into the cross-talk between the nervous and immune system. The study not only provided in vivo experiments to support their claim, but it also elucidated the role of iNKT cells in vitro, thereby further strengthening their support for their hypothesis. In addition, the results of the study have implications in post-stroke care as well as in the development of an effective therapy in post-stroke patients, where infection is the leading cause of death. Although antibiotics pose as a feasible option for treating infection in stroke patients, immunomodulation poses as another alternative. Indeed, finding the balance between an overactive immune system, which increases the likelihood of brain damage, and a suppressed immune system, which permits infection, is the key in establishing an effective therapy for post-stroke patients.
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Kimura, K., et al. "Mortality and Cause of Death After Hospital Discharge in 10,981 Patients with Ischemic Stroke and Transient Ischemic Attack." Cerebrovascular diseases (Basel, Switzerland) 19.3 (2005): 171-8. Print.
Langhorne, P., et al. "Medical Complications After Stroke: A Multicenter Study." Stroke; a journal of cerebral circulation 31.6 (2000): 1223-9. Print.
Trakhtenberg, E. F., and J. L. Goldberg. "Immunology. Neuroimmune Communication." Science (New York, N.Y.) 334.6052 (2011): 47-8. Print.
Wong, C. H., et al. "Functional Innervation of Hepatic iNKT Cells is Immunosuppressive
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