Abstract
Neuroinflammation is strongly induced by cerebral ischemia. The early phase after the onset of ischemic stroke is characterized by acute neuronal injury, microglial activation, and subsequent infiltration of blood-derived inflammatory cells, including macrophages. Therefore, modulation of the microglial/macrophage responses has increasingly gained interest as a potential therapeutic approach for the ischemic stroke. In our study, we investigated the effects of peripherally administered interleukin 13 (IL-13) in a mouse model of permanent middle cerebral artery occlusion (pMCAo). Systemic administration of IL-13 immediately after the ischemic insult significantly reduced the lesion volume, alleviated the infiltration of CD45+ leukocytes, and promoted the microglia/macrophage alternative activation within the ischemic region, as determined by arginase 1 (Arg1) immunoreactivity at 3 days post-ischemia (dpi). Moreover, IL-13 enhanced the expression of M2a alternative activation markers Arg1 and Ym1 in the peri-ischemic (PI) area, as well as increased plasma IL-6 and IL-10 levels at 3 dpi. Furthermore, IL-13 treatment ameliorated gait disturbances at day 7 and 14 and sensorimotor deficits at day 14 post-ischemia, as analyzed by the CatWalk gait analysis system and adhesive removal test, respectively. Finally, IL-13 treatment decreased neuronal cell death in a coculture model of neuroinflammation with RAW 264.7 macrophages. Taken together, delivery of IL-13 enhances microglial/macrophage anti-inflammatory responses in vivo and in vitro, decreases ischemia-induced brain cell death, and improves sensory and motor functions in the pMCAo mouse model of cerebral ischemia.
Highlights
Despite intensive research during the last decades, ischemic stroke remains a severely dementing and disabling disease with limited options of effective therapy and stands among the major causes of death worldwide
Because interleukin 13 (IL-13) can effectively trigger a shift from M1 to M2a state [11, 14] and attenuate the production of inflammatory mediators [11], we aimed to elucidate whether IL-13 is able to reduce neuroinflammation and protect from ischemia-induced brain damage
Analysis of GFAP immunoreactivity revealed that ischemic stroke upregulated the astrocyte activation significantly
Summary
Despite intensive research during the last decades, ischemic stroke remains a severely dementing and disabling disease with limited options of effective therapy and stands among the major causes of death worldwide. The primary neuroinflammatory response is initiated by immune cells, such as rapidly activated resident microglia and macrophages, resulting in the local production of inflammatory cytokines and chemokines. Secondary neuroinflammatory processes, widely initiated by polarized microglia and macrophages, astrocytes, and infiltrating peripheral leukocytes, can further aggravate the injury in the post-ischemic brain tissue [2]. During the early phase of stroke, activated microglia and infiltrated blood-derived macrophages secrete both pro- and anti-inflammatory factors, e.g., IL-1β, IL-6, tumor necrosis factor α (TNF-α), transforming growth factor beta (TGF-β), and activate pro-inflammatory enzymes, such as cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (NOS2/iNOS) [2,3,4]. The M2a profile has been associated with beneficial processes, such as neuroprotection, extracellular matrix remodeling and tissue repair, and increased phagocytic clearance of debris
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