Interleukin-10 (IL-10) is an important anti-inflammatory cytokine expressed in response to brain injury, where it facilitates the resolution of inflammatory cascades, which if prolonged causes secondary brain damage. Here, we comprehensively review the current knowledge regarding the role of IL-10 in modulating outcomes following acute brain injury, including traumatic brain injury (TBI) and the various stroke subtypes. The vascular endothelium is closely tied to the pathophysiology of these neurological disorders and research has demonstrated clear vascular endothelial protective properties for IL-10. In vitro and in vivo models of ischemic stroke have convincingly directly and indirectly shown IL-10-mediated neuroprotection; although clinically, the role of IL-10 in predicting risk and outcomes is less clear. Comparatively, conclusive studies investigating the contribution of IL-10 in subarachnoid hemorrhage are lacking. Weak indirect evidence supporting the protective role of IL-10 in preclinical models of intracerebral hemorrhage exists; however, in the limited number of clinical studies, higher IL-10 levels seen post-ictus have been associated with worse outcomes. Similarly, preclinical TBI models have suggested a neuroprotective role for IL-10; although, controversy exists among the several clinical studies. In summary, while IL-10 is consistently elevated following acute brain injury, the effect of IL-10 appears to be pathology dependent, and preclinical and clinical studies often paradoxically yield opposite results. The pronounced and potent effects of IL-10 in the resolution of inflammation and inconsistency in the literature regarding the contribution of IL-10 in the setting of acute brain injury warrant further rigorously controlled and targeted investigation.
Stroke and traumatic brain injury (TBI) are devastating acute neurological disorders that can result in high mortality rates or long-lasting disability. Approximately 87% of strokes are ischemic and 13% are hemorrhagic, with 10 and 3% of the latter representing intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH), respectively (1). Stroke is the fourth most common cause of death in the United States, and ischemic stroke (IS) in particular is the seventh most frequent emergency department presentation (2, 3). TBI and concussions have over twice the incidence of all strokes combined (4), with more than three million people in the United States alone living with long-term disability as a result of TBI (5). Collectively, stroke and TBI have very few treatments, and despite advances in clinical management of these disorders, they are still associated with significant disability and mortality (6, 7).
Inflammation plays a central role in the pathophysiology of stroke and TBI and can have both protective and harmful effects on brain tissue (8–15). Although there are some distinct differences in the inflammatory cascades following the various types of acute brain injury, there are also numerous commonalities. Acute neuroinflammation is characterized by the activation of resident central nervous system (CNS) immune surveillance glial cells that release cytokines, chemokines, and other immunologic mediators, which facilitate the recruitment of peripheral cells such as monocytes, neutrophils, and lymphocytes (8, 9, 12, 15). Collectively, this initial response is helpful in the clearance of toxic entities and the restoration and repair of damaged tissue. However, during the resolution phase, with an uncontrolled and prolonged inflammatory response, secondary damage results from overactivation of this inflammatory surge and release of additional factors that led to breakdown of the blood–brain barrier (BBB), cerebral edema, cerebral hypertension, and ischemia.
Interleukin-10 is generally known as an anti-inflammatory cytokine that exerts a plethora of immunomodulatory functions during an inflammatory response and is particularly important during the resolution phase. Expression of IL-10 in the brain increases with CNS pathology, promoting neuronal and glial cell survival, and dampening of inflammatory responses via a number of signaling pathways (16). IL-10 was originally described as cytokine synthesis inhibitory factor and in addition to attenuating the synthesis of proinflammatory cytokines, IL-10 also limits inflammation by reducing cytokine receptor expression and inhibiting receptor activation (16). Furthermore, IL-10 has potent and diverse effects on essentially all hematopoetic cells that infiltrate the brain following injury. For example, IL-10 reduces the activation and effector functions of T cells, monocytes, and macrophages, ultimately ending the inflammatory response to injury (17). The structure, function, and regulation of IL-10 have been extensively reviewed elsewhere, including a review of IL-10 in the brain (16–20), although not in the context of the various forms of acute brain injury. Please refer to the aforementioned reviews for additional details, including the potential cellular sources, target cells, signal transduction, and mode of action of IL-10.
Given the intriguing multifactorial role of IL-10 in the resolution of inflammatory cascades that are important for promoting neurologic recovery from acute brain injury, here we present a comprehensive literature review of preclinical and clinical studies in this area. We focus on the contribution of IL-10 in modulating various important parameters and pathophysiologic processes important for IS, SAH, ICH, and TBI outcomes, and whether IL-10 has therapeutic or biomarker potential. A better understanding of the many functions of IL-10 in the brain after injury, particularly in the resolution phase of inflammatory processes, will promote our knowledge of the pathophysiology of these debilitating disorders and guide future development of novel therapeutic approaches.[…]