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Review
. 2016 Jun 24;119(1):142-58.
doi: 10.1161/CIRCRESAHA.116.308022.

Inflammatory Disequilibrium in Stroke

Danica Petrovic-Djergovic  1 , Sascha N Goonewardena  1 , David J Pinsky  2
Affiliations
Review

Inflammatory Disequilibrium in Stroke

Danica Petrovic-Djergovic et al. Circ Res. .

Abstract

Over the past several decades, there have been substantial advances in our knowledge of the pathophysiology of stroke. Understanding the benefits of timely reperfusion has led to the development of thrombolytic therapy as the cornerstone of current management of ischemic stroke, but there remains much to be learned about mechanisms of neuronal ischemic and reperfusion injury and associated inflammation. For ischemic stroke, novel therapeutic targets have continued to remain elusive. When considering modern molecular biological techniques, advanced translational stroke models, and clinical studies, a consistent pattern emerges, implicating perturbation of the immune equilibrium by stroke in both central nervous system injury and repair responses. Stroke triggers activation of the neuroimmune axis, comprised of multiple cellular constituents of the immune system resident within the parenchyma of the brain, leptomeninges, and vascular beds, as well as through secretion of biological response modifiers and recruitment of immune effector cells. This neuroimmune activation can directly impact the initiation, propagation, and resolution phases of ischemic brain injury. To leverage a potential opportunity to modulate local and systemic immune responses to favorably affect the stroke disease curve, it is necessary to expand our mechanistic understanding of the neuroimmune axis in ischemic stroke. This review explores the frontiers of current knowledge of innate and adaptive immune responses in the brain and how these responses together shape the course of ischemic stroke.

Keywords: CD39; CD73; adaptive immunity; blood–brain barrier; brain ischemia; inflammation; innate immunity.

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Figures

Figure 1
Figure 1
Cellular composition of a mouse brain 48 hours after middle cerebral artery occlusion. The nonischemic (contralateral) and ischemic (ipsilateral) hemispheres were digested, cells isolated, and characterized by flow cytometry using discrete surface markers to identify the cell type. Note increasing presence of neutrophils and macrophages in the ischemic hemisphere relative to the non-ischemic hemisphere. Adapted from reference .
Figure 2
Figure 2
Infiltration of two populations of T Cells 48 hours after ischemic stroke. C represents the contralateral hemisphere, I represents the ipsilateral hemisphere. The presence of CD73, a 5’ectonucleotidase which cleaves AMP to generate adenosine, protects against both leukocyte influx and cerebral injury in stroke. Adapted from Reference .
Figure 3
Figure 3
Inflammatory disequilibrium after stroke. Following brain ischemia, circulating cells such as neutrophils, monocytes (innate immune cells), T-cells (adaptive immune cells), interact with platelets, causing sludging and cessation of cerebral blood flow, and tissue hypoxia. Acute ischemia refers to the early phases (minutes to hours) and delayed refers to late phases of the ischemic process (hours to days). Endothelial cell activation promotes immune cell transmigration into the injured brain parenchyma. In acute phase of brain ischemia, infiltrating immune cells (neutrophils, monocytes, dendritic cells, T-cells) and resident brain cells (microglia and astrocytes) are activated and promote tissue injury. Activated monocytes adhere to activated endothelium and following transmigration into the brain tissue transform into the blood-borne macrophages. Macrophages generate reactive oxygen intermediates, secrete pro-inflammatory cytokines, upregulate costimulatory molecules (CD80 shown here), and create a pro-thrombotic environment. Similarly, microglia migrates toward the lesion site early on after the insult and secretes pro-inflammatory mediators that cause additional injury; however, microglia promotes tissue repair and remodeling through debris phagocytosis. Astrocytes can secrete both-pro-inflammatory (CXCL10, MCP-1) as well anti-inflammatory (IL-10, TGF-β) chemokines/cytokines to promote injury or repair, respectively; IL-23 produced by macrophages/microglia activate γδT-cells, which contributes to tissue injury via secretion of IL-17; Naïve T-cells (CD4/CD8) contribute to brain injury in an antigen un-specific manner, possibly via INF-γ, ROS and perforin. Other T-cells such as T-regulatory cells (T-regs) induce brain tissue repair via IL-10 secretion, inhibition of the effector T-cells response, neurogenesis and CNS tissue antigen tolerization. In the delayed phase after brain ischemia, antigen presenting cells (APC i.e. macrophages, microglia, astrocytes, and dendritic cells (not depicted in the schematic) present CNS antigens to CD4+ or CD8+ T-cells in antigen specific manner in context of MHC class I or II. Purinergic mediators such as ATP and adenosine act as an extracellular “danger” signals differentially influencing immune responses in stroke. Ectoenzymes, CD39 and CD73 act in tandem to dissipate pro-inflammatory and generate anti-inflammatory mediators. Brain resident cells and certain immune cells express these ectoenzymes.
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