Low-dose interleukin-2 alleviates neuroinflammation and improves cognitive impairment in high-fat diet mice

Abstract

Abstract Background Interleukin-2 was originally thought to be a proinflammatory factor, but recent studies have revealed that low-dose interleukin-2 might have an anti-inflammatory property. The aim of the study was to reveal whether the cytokine inhibited neuroinflammation in a high-fat diet mouse model and to further reveal the mechanism involved. Methods Mice were treated with a single administration of an AAV-interleukin-2 or AAV-LUC vector. Then, the mice were fed a normal or high-fat diet for 12 weeks, followed by a 4-week intervention period. During the intervention period, some of the mice were treated with CREB inhibitor 666 − 15. Then, cognitive function and depression-like behavior were assessed using the Morris water maze, sucrose preference test and tail suspension test. The expression of p-CREB, several microglial polarizations and inflammasome markers were measured using western blotting. The rate of pyroptosis and expansion and activation of Tregs were assessed using flow cytometry. Results A high-fat diet caused cognitive impairment and depression-like behavior in the mice. Meanwhile, the high-fat diet also inhibited the expansion and activation of Tregs, promoted microglial M1 polarization, activated the NLRP3 inflammasome and pyroptosis in the hippocampus, and eventually induced significant neuroinflammation in the hippocampus. Low-dose IL-2 using an AAV vector reversed these cognitive, behavioral and pathophysiological abnormalities. However, 666 − 15 treatment weakened the protective effect of IL-2 and aggravated cognitive impairment, neuroinflammation and all other abnormalities in the mice. Conclusion Low-dose interleukin-2 alleviated neuroinflammation and cognitive impairment by activating CREB signaling in high-fat diet mice.