Immune Modulation as a Key Mechanism for the Protective Effects of Remote Ischemic Conditioning After Stroke

Abstract

Remote ischemic conditioning (RIC), which involves a series of short cycles of ischemia in an organ remote to the brain (typically the limbs), has been shown to protect the ischemic penumbra after stroke and reduce ischemia/reperfusion (IR) injury. Although the exact mechanism by which this protective signal is transferred from the remote site to the brain remains unclear, preclinical studies suggest that the mechanisms of RIC involve a combination of circulating humoral factors and neuronal signals. An improved understanding of these mechanisms will facilitate translation to more effective treatment strategies in clinical settings. In this review, we will discuss potential protective mechanisms in the brain and cerebral vasculature associated with RIC. We will discuss a putative role of the immune system and circulating mediators of inflammation in these protective processes, including the expression of pro-and anti-inflammatory genes in peripheral immune cells that may influence the outcome. We will also review the potential role of extracellular vesicles (EVs), biological vectors capable of delivering cell-specific cargo such as proteins and miRNAs to cells, in modulating the protective effects of RIC in the brain and vasculature.

Remote Ischemic Conditioning: Challenges and Opportunities

“…Among the multiple candidates that have been proposed as putative mediators of the protective effects of RIC, the extracellular vesicles (small endogenous particles that contain cytokines, chemokines, genetic material, and many more biological substrates) can facilitate the transfer of protective effects of RIC through the flow stream, and allow them to interconnect distant cells, tissues, or organs and affect the target cells’ transcriptional profiles and likely their function and phenotype. 16 The above stimulus can subsequently deliver either proinflammatory or anti-inflammatory factors, and modulate the immune response. In addition, a number of mainly preclinical studies have demonstrated that the presence of certain comorbidities (such as age, metabolic syndrome, and hypertension) and comedications (such as statin) may interfere with the cardioprotective and neuroprotective effect of conditioning protocols such as RIC, and this should also be taken into consideration when interpreting the results from different trials.…”

Assessment of remote ischemic conditioning delivery with optical sensor in acute ischemic stroke: Randomised clinical trial protocol

“…Further studies showed transient cyclical ischemia-reperfusion to a limb muscles or in a remote organ can offer protection not only against heart, but also other organs including brain, liver, and kidneys [ 7 – 10 ]. The mechanism of action of remote ischemic conditioning is through humoral, neural and immunomodulatory pathways [ 11 ]. Early-phase 2 and a few phase 3 human clinical trials on RIC in ischemic stroke have been promising so far [ 12 – 15 ].…”

The Role of Connexin Hemichannels in Inflammatory Diseases

“…Tissue injuries caused by ischemia or ischemia–reperfusion (IR) can be separated into two phases: the first is caused directly by hypoxia and hypoglycemia during blood vessel occlusion, and the second is attributable to the ensuing inflammation [ 119 , 120 ]. DAMPs released from injured cells in the first phase play a major part in triggering and intensifying inflammation in the vicinity of ischemic loci [ 120 ].…”