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

Abstract

Most psychiatric and neurological diseases are exacerbated by stress. Because this may partially result from stress-induced inflammation, we examined factors involved in this stress response. After a paradigm of inescapable foot shock stress that causes learned helplessness depression-like behavior, eighteen cytokines and chemokines increased in mouse hippocampus, peaking 6 to 12 hr after stress. A 24 hr prior pre-conditioning stress accelerated the rate of stress-induced hippocampal cytokine and chemokine increases, with most reaching peak levels after 1 to 3 hr, often without altering the maximal levels. Toll-like receptor 4 (TLR4) was involved in this response because most stress-induced hippocampal cytokines and chemokines were attenuated in TLR4 knockout mice. Stress activated glycogen synthase kinase-3 (GSK3) in wild-type mouse hippocampus, but not in TLR4 knockout mice. Administration of the antidepressant fluoxetine or the GSK3 inhibitor TDZD-8 reduced the stress-induced increases of most hippocampal cytokines and chemokines. Stress increased hippocampal levels of the danger-associated molecular pattern (DAMP) protein high mobility group box 1 (HMGB1), activated the inflammatory transcription factor NF-κB, and the NLRP3 inflammasome. Knockdown of HMGB1 blocked the acceleration of cytokine and chemokine increases in the hippocampus caused by two successive stresses. Fluoxetine treatment blocked stress-induced up-regulation of HMGB1 and subsequent NF-κB activation, whereas TDZD-8 administration attenuated NF-κB activation downstream of HMGB1. To test if stress-induced cytokines and chemokines contribute to depression-like behavior, the learned helplessness model was assessed. Antagonism of TNFα modestly reduced susceptibility to learned helplessness induction, whereas TLR4 knockout mice were resistant to learned helplessness. Thus, stress-induces a broad inflammatory response in mouse hippocampus that involves TLR4, GSK3, and downstream inflammatory signaling, and these stress responses contribute to susceptibility to depression-like behavior in mice.

Stressed and Inflamed, Can GSK3 Be Blamed?

“…Recently it was found that psychological stress-induced activation of GSK3 is intimately linked to inflammation, as blocking signaling through TLR4 blocked the activation of GSK3 by stress. Blocking this signaling through TLR4 and GSK3 also decreased stress-induced inflammation, and nearly eliminated the development of depressive symptoms in mice [15]. Thus, susceptibility to depressive characteristics in rodents, and perhaps depression in humans, is promoted by psychological stress-induced signaling through TLR4 that activates GSK3 and neuroinflammation.…”

“…In the brain, the cytosolic inflammasome complex containing NLRP3 has particularly received attention because it is activated in microglia, macrophages and astrocytes in response to psychological stress. Activation of NLRP3 after psychological stress has been associated with depression-like behaviors [15,47-49]. For example, NLRP3 in the brain was increased by treatments that can increase depression-like behaviors, including inescapable tail shocks [50] and by chronic unpredictable mild stress, which was blocked by treatment with the antidepressant fluoxetine [51].…”

“…GSK3β activates the NLRP3/IL-1β pathway in lupus nephritis [53]. Psychological stress-induced activation of GSK3β leads to activation of the NLRP3/IL-1β pathway [15,54]. Thus, NLRP3 inflammasome activation is another mechanism, in addition to TLR-mediated signaling, that is stimulated by psychological stress, utilizes activated GSK3, and increases inflammatory cytokines in the brain.…”

Checks and balances: The glucocorticoid receptor and NFĸB in good times and bad

“…In the absence of overt inflammation in the central nervous system (CNS), stress is capable of activating inflammatory signaling pathways via release of danger/damage-associated molecular patterns (DAMPs) and microbe-associated molecular patterns (MAMPs) that bind to immune receptors, a process termed “sterile inflammation” (Fleshner 2013, Slavich and Irwin 2014). High mobility group box 1 (HMGB1), one of the best-characterized DAMPs, resides undetected in the nucleus of a cell when unstimulated but is released upon activation as demonstrated in a rodent model of inescapable footshock stress (Cheng, Pardo et al 2016). The released HMGB1 protein can signal through toll-like receptors (TLRs) present primarily on microglia to activate these cells and further promote the spread of inflammation in the brain via NFκB signaling (Weber, Frank et al 2015, Cheng, Pardo et al 2016).…”

The Role of HMGB1 in Pial Arteriole Dilating Reactivity following Subarachnoid Hemorrhage in Rats

“…HMGB1 is a central player in the inflammatory network because it can be induced by a number of cytokines, and itself induces a series of inflammatory reactions [3]. The activation of both RAGE and TLR4 can induce neuroinflammation, contributing to the development of neurodegenerative diseases [4,5,6]. Neuroinflammation has also been associated with the induction of cerebral vasoconstriction following subarachnoid hemorrhage (SAH) [7,8,9].…”