This study of EVT participants from the AISRNA study showed a strong association of IL-6 and IL-10 levels on admission with risk of END. Our study suggested that patients with increased IL-6 and IL-10 levels had higher risks of developing post-EVT END. By contrast, there was no correlation of baseline levels of IL-2, Il-4, INF-γ, and TNF-α with END. The predictive power of IL-6 for END was superior to that of other inflammatory factors. Additionally, IL-4, IL-6, and IL-10 levels presented a marked rising trend in patients with END.
Inflammation is a hallmark of stroke etiology and progression. Post-stroke inflammation is accounted as a requisite pathological process involved in ischemic brain injury (12). A series of detrimental complications occur and the blood-brain barrier (BBB), damaged after the initial brain injury, crossed by activated peripheral immune cells including monocytes and T-cells (13). Furthermore, post-stroke inflammatory response is associated with stroke severity on admission as determined by NIHSS (14). Additionally, patients who underwent END were more susceptible to have a poor functional outcome after 90 days (15). However, the association between post-stroke inflammatory response and END remains uncertain. Therefore, we performed a prospective study from the AISRNA study to further investigate the influence of inflammatory factors on END after stroke.
The biological function of IL-6 in AIS remains unclear. Mounting evidence have demonstrated that IL-6 levels are increased in peripheral blood samples during the first 7 days after stroke onset. For example, increased IL-6 was associated with the infarct size and stroke severity on admission (16) as well as risk of incident stroke (17), although a study reported the opposite that early IL-6 levels, as a neuroprotective factor, was inversely correlated with lesion size and functional outcome (18). Our findings also suggested that increased IL-6 was associated with risk of END after EVT. However, there is a less agreement on the time point of peak IL-6 levels. Some studies reported IL-6 peak levels at 3 day (19, 20), which are similar to our findings. Other describe high levels of IL-6 with ranged from a few hours till one day or first week after stroke (18, 21, 22).
We also reported positive correlation between IL-10 and END after EVT. Previous studies have suggested IL-10 as a marker for incident stroke (23, 24). IL-10 is a major anti-inflammatory cytokine to regulate the immune response by suppressing pro-inflammatory cytokine expression. The influence of IL-10 on functional outcome and its time course after EVT remains uncertain. Several investigators reported that IL-10 may serve a neuroprotective role and predict clinical outcome after stroke (25, 26). However, our previous studies from the experimental rats and human stroke patients observed that IL-10 was positively associated with stroke risk (27, 28). In the current study, increased IL-10 levels on admission were associated with END after EVT. Whereas we observed IL-10 peak levels at 2 days, and patients with END had decreased IL-10 levels compared with those with non-END at 7 days. This phenomenon may be due to a stress response of IL-10 regarding END which lead high levels of IL-10, but its levels were subsequently decreased after 2 days. Therefore, IL-10 may be involved in the process of END, and its molecular mechanisms remain to be explored in the further study.
IL-4, an anti-inflammatory cytokine, can drive Th2 cell differentiation which plays beneficial roles in inhibiting post-stroke inflammation, repairing damaged brain tissues and inducing neurotrophic factors in astrocytes (29, 30). A previous study has demonstrated that IL-4 was significantly correlated with stroke severity and functional outcome in AIS patients (31). However, our results showed no association of IL-4 with END after EVT, but IL-4 levels were increased in patients with END at 2 days and then rapidly decreased at 3 days. At present, we are also investigating its molecular mechanisms regarding dynamic change of IL-10 in stroke progression.
Several limitations should be acknowledged in the study. First, this is a small number of patients in a single center, but we are seeking for sub-centers to complete the AISRNA study. Second, we did not analyze the association between initial infarct burden and END after EVT. Finally, molecular mechanisms regarding dynamic changes of these inflammatory factors should be further explored in patients undergoing EVT.