Abstract
NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome inhibition and autophagy induction attenuate inflammation and improve outcome in rodent models of cerebral ischemia. However, the impact of chronic stress on NLRP3 inflammasome and autophagic response to ischemia remains unknown. Progesterone (PROG), a neuroprotective steroid, shows promise in reducing excessive inflammation associated with poor outcome in ischemic brain injury patients with comorbid conditions, including elevated stress. Stress primes microglia, mainly by the release of alarmins such as high-mobility group box-1 (HMGB1). HMGB1 activates the NLRP3 inflammasome, resulting in pro-inflammatory interleukin (IL)-1β production. In experiment 1, adult male Sprague-Dawley rats were exposed to social defeat stress for 8 days and then subjected to global ischemia by the 4-vessel occlusion model, a clinically relevant brain injury associated with cardiac arrest. PROG was administered 2 and 6 h after occlusion and then daily for 7 days. Animals were killed at 7 or 14 days post-ischemia. Here, we show that stress and global ischemia exert a synergistic effect in HMGB1 release, resulting in exacerbation of NLRP3 inflammasome activation and autophagy impairment in the hippocampus of ischemic animals. In experiment 2, an in vitro inflammasome assay, primary microglia isolated from neonatal brain tissue, were primed with lipopolysaccharide (LPS) and stimulated with adenosine triphosphate (ATP), displaying impaired autophagy and increased IL-1β production. In experiment 3, hippocampal microglia isolated from stressed and unstressed animals, were stimulated ex vivo with LPS, exhibiting similar changes than primary microglia. Treatment with PROG reduced HMGB1 release and NLRP3 inflammasome activation, and enhanced autophagy in stressed and unstressed ischemic animals. Pre-treatment with an autophagy inhibitor blocked Progesterone’s (PROG’s) beneficial effects in microglia. Our data suggest that modulation of microglial priming is one of the molecular mechanisms by which PROG ameliorates ischemic brain injury under stressful conditions.
Highlights
Chronic stress has been implicated in increasing the risk of cardiovascular events, including cardiac arrest and worsening outcomes [1,2,3]
At 14 days post-ischemia, serum high-mobility group box-1 (HMGB1) returned to basal levels (Figure 1A), while HMGB1 levels remained elevated in the hippocampus of stressed and unstressed ischemic animals (Figure 1B, C)
MGolr. eSdciu. 2c0e2d0, p21e,r3ip74h0eral and hippocampal HMGB1 release induced by global ischemia, which3wofa2s1 worsened by comorbid stress (Figure 1A-C)
Summary
Chronic stress has been implicated in increasing the risk of cardiovascular events, including cardiac arrest and worsening outcomes [1,2,3]. Increasing evidence indicates that microglial overactivation leads to exacerbated neuronal damage and excessive brain inflammation in stressed ischemic animals [6,7,8,9,10,11]. From a translational perspective, reducing the neurotoxic potential of primed microglia has important implications for the treatment of ischemic brain injury patients with elevated stress. Stress-induced microglial priming is mediated by an alarmin called high-mobility group box-1 (HMGB1) [12]. HMGB1 is a ubiquitous nuclear protein that can be released in the brain either by inflammatory cells in response to stress [13,14] or by necrotic cells following ischemic brain injury [15,16,17,18]. Once released into the extracellular space, HMGB1 binds to its receptors and triggers the activation of the inflammasomes [21]
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