NLRP3 Inflammasome Mediates Chronic Mild Stress-Induced Depression in Mice via Neuroinflammation

Abstract

Background:Evidence from both clinical and experimental research indicates that the immune-brain interaction plays a pivotal role in the pathophysiology of depression. A multi-protein complex of the innate immune system, the NLRP3 inflammasome regulates cleavage and secretion of proinflammatory cytokine interleukin-1β. The inflammasome detects various pathogen-associated molecule patterns and damage-associated molecule patterns, which then leads to a series of immune-inflammatory reactions.Methods:To explore the role of inflammasome activation in the underlying biological mechanisms of depression, we established a mouse model of depression with unpredictable chronic mild stress.Results:Mice subjected to chronic mild stress for 4 weeks had significantly higher serum corticosterone levels, serum interleukin-1β levels, and hippocampal active interleukin-1β protein levels. They also displayed depressive-like symptoms, including decreased sucrose preference and increased immobility time. Moreover, the hippocampi of chronic mild stress-exposed mice had significantly higher activity of caspase-1, which accompanied by higher protein levels of NLRP3 and the apoptotic speck-containing protein with a card. Pretreatment with the NLRP3 inflammasome inhibitor VX-765 decreased serum and hippocampal levels of interleukin-1β protein and significantly moderated the depressive-like behaviors induced by chronic mild stress.Conclusions:These data suggest the NLRP3 inflammasome mediates stress-induced depression via immune activation. Future procedures targeting the NLRP3 inflammasome may have promising effects in the prevention and treatment of depression.

Anti-depressant-like effect of atractylenolide I in a mouse model of depression induced by chronic unpredictable mild stress

“…Therefore, together with the results of the neurotransmitter assay, the results of the present study suggested that AT-I may ameliorate CUMS-induced depression in mice via inhibition of IL-1β production. Furthermore, the NLRP3 inflammasome, an important regulator of IL-1β transcription and function, has been proved to be involved in stress-induced depression (10). As observed in the present study, a 3-week CUMS procedure significantly activated the NLRP3 inflammasome, as evidenced by significantly increased NLRP3 and ASC protein levels as well as caspase-1 maturation, which is in agreement with a previous study (31).…”

“…A previous study reported that activated NLRP3 inflammasome along with increased serum levels of IL-1β and IL-18 were observed in mononuclear blood cells from patients with major depressive disorder (8). Furthermore, the NLRP3 inflammasome was demonstrated to mediate IL-1 β-associated central nervous system (CNS) inflammation in animal models of stress-induced depression (9,10). All of the above suggested a key role of the NLRP3 inflammasome in the development of depression.…”

Chronic stress exacerbates neuronal loss associated with secondary neurodegeneration and suppresses microglial-like cells following focal motor cortex ischemia in the mouse

“…As mentioned previously, several studies have already indicated that exposure to stress in the absence of injury can result in increased trafficking of monocytes into the brain (Reader et al, 2015;Wohleb et al, 2011Wohleb et al, , 2013Wohleb et al, , 2014. Other studies have also provided compelling evidence that stress can, by itself, lead to an enhancement of neuroinflammatory signaling and a potentiation of microglial functions (de Pablos et al, 2014;Sorrells et al, 2013;Zhang et al, 2015). In contrast to these findings there have been several reports indicating that stress can suppress neuroinflammatory activity, as well as myelopoiesis (Chantong et al, 2012;Nakatani et al, 2012;Queiroz Jde et al, 2013;Sugama et al, 2009bSugama et al, , 2013a.…”

Stress-induced neuroinflammation is mediated by GSK3-dependent TLR4 signaling that promotes susceptibility to depression-like behavior

“…For example, chronic mild stress increased NLRP3 levels, active caspase-1, and hippocampal IL-1β levels, and a NLRP3 inflammasome inhibitor reduced stress-induced IL-1β increases (Pan et al, 2014;Zhang et al, 2015). In addition, chronic corticosterone treatment that mimics stress increased NLRP3 levels in the hippocampus .…”