In this study, we conducted a two-sample Mendelian randomized analysis using a GWAS database to explore the causal relationship between inflammatory cytokines and stroke and its subtypes in 41 patients. In this study, some suggestive evidence was obtained: for example, low level of TRAIL, high level of IL-4, IL-1β, IL-12p70, and VEGF may be related to the occurrence of IS, high level of IP-10 may be related to the occurrence of LICH and low level of IL-17 may be related to NLICH. These findings were robust in sensitivity analysis, and our MR results showed a causal relationship between inflammatory factors and stroke risk.
Acute IS and ICH affect millions of people worldwide. Previous studies have shown that stroke leads to acute focal brain injury. As the ischemic time prolongs, the damaged nerve cells produce a large amount of reactive oxygen species, and glial cells secrete a large amount of cytokines, leading to nerve cell death and the destruction of the blood-brain barrier. Immune cells activated in the periphery accumulate in the ischemic brain tissue through the damaged blood-brain barrier.[21–24]. Although the pathogenesis of the primary injury is different, the activation of the immune response occurs similarly in IS and ICH. Damaged cells release damage-associated molecular patterns that trigger the immune response, which mediate the activation of intracellular signaling pathways through a series of complex processes[22]. ILs play a bidirectional role in the occurrence and development of IS[25]. On the one hand, it can mediate the activation, reproduction, and differentiation of T and B cells, and on the other hand, it can activate and regulate the inflammatory response of inflammatory cells through signal transduction[7, 9, 26]. Among them, IL-4 increases significantly during the acute phase of stroke, promoting the polarization of M2 microglia, inhibiting pro-inflammatory cytokines, and affecting neuronal excitability[27]. It has been reported that infarct size after an ischemic stroke can be reduced by IL-4 secreted by M2 microglia and can contribute to recovery postmortem[28]. After activation of microglia by IL-4, it can accelerate angiogenesis by secreting extraneous bodies containing miRNA-26a, thereby alleviating IS damage[9, 29].
IL-1β is a pro-inflammatory cytokine with neurotoxic effects although other inflammatory factors may cause stroke. Research has indicated that elevated release of IL-1β has the ability to trigger phospholipase A2, causing the breakdown of arachidonic acid and disruption of the phospholipid bilayer, ultimately resulting in dysfunction of the blood-brain barrier. The interaction between IL-1β and vascular endothelium can enhance the adherence of leukocytes. At the same time, IL-1β can enhance ischemic injury by activating the molecular mechanism of apoptosis, leading to the apoptosis of damaged cells[30]. Most cell types, such as neurons, astrocytes, and endothelial cells, secrete VEGF, which is believed to play a role in angiogenesis and the permeability of blood vessels. Research has indicated that VEGF is significantly stimulated in the hyperacute stage of cerebral ischemia, contributing not only to enhancing vascular permeability and facilitating angiogenesis but also to playing a crucial part in neuroprotection[31]. Microglia release TRAIL, a member of the TNF superfamily. Experimental evidence suggests that TRAIL exerts its neuroprotective effect by increasing the expression of TRAIL bait receptors and decreasing the expression of TRAIL itself and its death receptors[32]. GROα is a pro-inflammatory chemokine that interacts with other cytokines and expresses adhesion molecules after stroke, thus promoting white blood cell migration to ischemic sites[33]. The secretion of IL-17 by Th17 cells stimulates T-cell activation by causing the production of different inflammatory cytokines, leading to a strong inflammatory reaction. This reaction could potentially be a significant factor in the development of ICH[25]. The interaction between cytokines and inflammatory cells, as well as the interaction among cytokines, can impact the onset and progression of stroke, and even influence the outcome of stroke patients[34]. Inflammatory factors play important roles in the immune mechanisms underlying stroke.
Our study had some limitations. First, our GWAS data were from a European population, and it remains to be proven whether the results of this study are consistent across populations in different regions. Second, we used relatively high thresholds (p < 5 × 10− 6) when extracting IVs, and there may be a weak IV bias. However, given the F-statistics, we can ignore the effect of weak IVs on the results. In addition, we investigated only the association between systemic inflammation and neuroinflammation, which may have different effects on stroke and its subtypes. Thus, obtaining high-quality neuroinflammatory GWAS will be valuable in the future. Finally, in our MR Analysis, we were unable to analyze all inflammatory cytokines due to the exclusion criteria and previous GWAS, which had a limited number of these cytokines.