Paradigm Shift to Neuroimmunomodulation for Translational Neuroprotection in Stroke

Abstract

The treatment of acute ischemic stroke is still an unresolved clinical problem since the only approved therapeutic intervention relies on early blood flow restoration through pharmacological thrombolysis, mechanical thrombus removal, or a combination of both strategies. Due to their numerous complications and to the narrow time-window for the intervention, only a minority of stroke patients can actually benefit from revascularization procedures, highlighting the urgent need of identifying novel strategies to prevent the progression of an irreversible damage in the ischemic penumbra. During the past three decades, the attempts to target the pathways implicated in the ischemic cascade (e.g., excitotoxicity, calcium channels overactivation, reactive oxygen species (ROS) production) have failed in the clinical setting. Based on a better understanding of the pathobiological mechanisms and on a critical reappraisal of most failed trials, numerous findings from animal studies have demonstrated that targeting the immune system may represent a promising approach to achieve neuroprotection in stroke. In particular, given the dualistic role of distinct components of both the innate and adaptive arms of the immune system, a strategic intervention should be aimed at establishing the right equilibrium between inflammatory and reparative mechanisms, taking into consideration their spatio-temporal recruitment after the ischemic insult. Thus, the application of immunomodulatory drugs and their ability to ameliorate outcomes deserve validation in patients with acute ischemic stroke.

Keywords: brain ischemia; immune system; inflammation; ischemic cascade; neuroprotection; stroke.

Figure 1

Polarization of microglia/macrophages toward protective (M2) or inflammatory (M1) phenotypes after ischemic stroke. Early after the ischemic insult, locally activated microglia/macrophages and blood-borne monocytes/macrophages display an M2 phenotype characterized by enhanced phagocytic activity and production of mediators [e.g., IL-10, transforming growth factor (TGF)-β, arginase] that provide resolution of inflammation and pro-survival effects toward hypoxic/ischemic neurons. This M2-mediated response is transient and quenches few days after the insult, being replaced by an inflammatory detrimental phase dominated by M1-polarized cells that exhibit reduced phagocytosis ability and release of inflammatory and neurotoxic mediators (e.g., TNF-α, IL-1β, IL-6, MCP-1, MIP-1α, proteases, ROS, nitric oxide). At later stages, release of regulatory and growth factors [e.g., brain-derived neurotrophic factor (BDNF), glia-derived neurotrophic factor (GDNF), and insulin-like growth factor (IGF)-1] by M2-like microglia/macrophages contributes to reparative mechanisms implicated in late tissue recovery. The M1/M2 dichotomy is an illustrative theoretical framework that only embodies two extreme activation states of a spectrum of different functional phenotypes that actually occur in the damaged tissue. The inflammatory M1 phenotypes are typically triggered by interferon (INF)-γ, TLRs modulation or miRNA-155; whereas, the reparative M2 phenotypes are prompted by IL-4, IL-10, TGF-β, miRNA-124, or miRNA-145. Moreover, a number of receptors have been demonstrated to trigger polarization toward the M2 or M1 phenotype, thus representing promising targets for successful immunomodulation in stroke: the α7 nicotinic acetylcholine receptor (α7 nAChR), the CD200R, the peroxisome proliferator-activated receptor-γ (PPARγ), the triggering receptor expressed on myeloid cells (TREM), the class A scavenger receptor (SR-A), the fractalkine receptor CX3CR1 and the mineralcorticoid receptor (MR).