NLRP3 inflammasome-IL-1β-IL-1R1 signaling pathway is involved in surgery- induced neuroinflammation in mice

Abstract

OBJECTIVE Previous studies have shown that the activation of NLRP3 inflammasome and associated IL-1β/IL-1R1 pathway plays a crucial role in the occurrence and development of inflammation-induced impairment of diverse diseases, inflammation-induced pulmonary fibrosis pathological process. However, the impact of NLRP3 inflammasome-IL-1β-IL-1R1 signaling pathway in surgery-induced neuroinflammation still remains unknown. METHODS Firstly, male C57BL/6J mice were adopted to randomly devided into control group and different time point group (0.5h, 6h, 12h, 18h, 24h) after surgery treated with carotid artery exploration surgery. Moreover, to further investigate the effect of blockage of NLRP3, 4 groups including control group, surgery group, surgery + AAV group and surgery + NEG group, were added to our experiments. After the surgery, the levels of proteins related to the NLRP3 inflammasome, IL-1R1, IL-1β, and IL-18 in diverse groups were measured by immunofluorescence assay, quantitative polymerase chain reaction (qPCR), western blot, and enzyme-linked immunosorbent assay (ELISA), respectively. Microglia and monocytes were separately determined by flow cytometry. The pathological changes in the brain were detected by Nissl staining. RESULTS Peripheral surgery resulted in monocyte activation and an increase in the expression of IL-1β in the circulatory system. IL-1R1, NLRP3, activated caspase-1 (caspase-1 P10), IL-1β, and IL-18 were upregulated in the hippocampus. Subsequently, the expression of microglia cells considerably increased and neuronal damage was observed. These effects were attenuated by AAV-NLRP3 treatment. CONCLUSIONS The peripheral surgery induced an increase of IL-1β, IL-1R1, NLRP3, and neuron injury in the hippocampus, inhibiting the expression of NLRP3 can alleviate inflammatory factors expression and neuron damage. We assumed that there is a feedback mechanism about IL-1β-IL-1R1-NLRP3 inflammasome existing in the brain after peripheral surgery.