Inhibition of NLRP3 Inflammasome Ameliorates Cerebral Ischemia-Reperfusion Injury in Diabetic Mice

Peng, Hong; Li, Fengxian; Gu, Ruonan; Fang, Yunxia; Lai, Luhua; Wang, Yongwei; Tao, Tao; Xu, Shiyuan; Zhang, You; Zhang, Hongfei

doi:10.1155/2018/9163521

Cited by 53 publications

(46 citation statements)

References 28 publications

(27 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There are few studies regarding these diseases and the NLRP3 inflammasome. Our study found that MCC950 can improve prognosis in diabetic mice with stroke [ 96 ], which is consistent with other research. MCC950 mitigated Aβ pathology and therefore improved cognition by suppressing NLRP3 inflammasome activation and increasing the phagocytic capability of microglia [ 111 ].…”

Section: Potential For Targeting the Nlrp3 Inflammasome For Treating supporting

confidence: 93%

“…As mentioned above, the NLRP3 inflammasome is an important factor in inflammatory injury after stroke, but whether it is the leading factor for deteriorating diabetic-stroke remains an unanswered question. Based on this background, we previously established a mouse model of T2DM and MCAO and found that treatment with the NLRP3-specific inhibitor MCC950 alleviated neurological deficits and improved long-term survival [ 96 ]. In addition, mRNA levels of IL-1β/NLRP3 were significantly elevated in the ischemic brain, but were lower when treated with MCC950.…”

Section: Potential For Targeting the Nlrp3 Inflammasome For Treating mentioning

confidence: 99%

See 1 more Smart Citation

NLRP3 inflammasome as a potential treatment in ischemic stroke concomitant with diabetes

Peng

et al. 2019

J Neuroinflammation

Self Cite

112

View full text Add to dashboard Cite

The NLRP3 (nucleotide-binding oligomerization domain-like receptor [NLR] family pyrin domain-containing 3) inflammasome is a member of the NLR family of innate immune cell sensors. These are crucial regulators of cytokine secretions, which promote ischemic cell death and insulin resistance. This review summarizes recent progress regarding the NLRP3 inflammasome as a potential treatment for ischemic stroke in patients with diabetes, two complicated diseases that often occur together. Stroke worsens glucose metabolism abnormalities, and the outcomes after stroke are more serious for diabetic patients compared with those without diabetes. Inflammation contributes to organ injury after ischemic stroke and diabetes. Recent research has focused on inhibiting the activation of inflammasomes and thus reducing the maturation of proinflammatory cytokines such as interleukin (IL)-1β and IL-18. Studies suggest that inhibition of NLRP3 prevents or alleviates both ischemic stroke and diabetes. Targeting against the assembly and activity of the NLRP3 inflammasome is a potential and novel therapy for inflammasome-associated diseases, including ischemic stroke concomitant with diabetes.

show abstract

Section: Potential For Targeting the Nlrp3 Inflammasome For Treating supporting

confidence: 93%

Section: Potential For Targeting the Nlrp3 Inflammasome For Treating mentioning

confidence: 99%

NLRP3 inflammasome as a potential treatment in ischemic stroke concomitant with diabetes

Peng

et al. 2019

J Neuroinflammation

Self Cite

112

View full text Add to dashboard Cite

show abstract

“…In our study, NLRP3 inflammasome activation peaked at 14 days post-ischemia. In line with our results on comorbid stress combined with global ischemia, Hong et al [59] found that comorbid diabetes remarkably amplifies NLRP3, caspase-1, and IL-1β expression in the ischemic core. Collectively, these data reinforce the idea that inflammation-related comorbidities such as comorbid stress and diabetes, drive NLRP3 inflammasome priming associated with worsening ischemic brain injury.…”

Section: Effects Of Stress Exposure Prior To Ischemia On Nlrp3 Inflamsupporting

confidence: 92%

Progesterone Attenuates Stress-Induced NLRP3 Inflammasome Activation and Enhances Autophagy Following Ischemic Brain Injury

Espinosa‐García

Atif

Yousuf

et al. 2020

IJMS

View full text Add to dashboard Cite

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.

show abstract

“…Finally, we found that administration of MCC950 protected against cholestasis induced fibrosis. Since MCC950 was proven to have a protective function in various other injury models and diseases, such as colitis, lung ischemia-reperfusion and traumatic brain injury, it is likely that there is a potential therapeutic function in human cholestatic liver and kidney injury 38,53,54 . Hence, it might be interesting to introduce Nlrp3 inhibitors in humans with chronic cholestatic liver injury e.g.…”

Section: Accepted Articlementioning

confidence: 99%

Bidirectional Role of NLRP3 During Acute and Chronic Cholestatic Liver Injury

et al. 2021

View full text Add to dashboard Cite

Nothing to disclose Author Contributions: MF wrote the manuscript and performed all liver experiments, LL performed BDL and helped sacrificing animals, KMS performed FACS analysis and helped sacrificing animals, JH provided the human PBC samples and stainings, SD performed the kidney experiments, AW provided inflammasome-related critical revision, URK and MB performed the bile acid analysis, PB reviewed stainings and provided critical revision, CT provided funding, concept and design of the work as well as critical revision.

show abstract

Inhibition of NLRP3 Inflammasome Ameliorates Cerebral Ischemia-Reperfusion Injury in Diabetic Mice

Cited by 53 publications

References 28 publications

NLRP3 inflammasome as a potential treatment in ischemic stroke concomitant with diabetes

NLRP3 inflammasome as a potential treatment in ischemic stroke concomitant with diabetes

Progesterone Attenuates Stress-Induced NLRP3 Inflammasome Activation and Enhances Autophagy Following Ischemic Brain Injury

Bidirectional Role of NLRP3 During Acute and Chronic Cholestatic Liver Injury

Contact Info

Product

Resources

About