CD73 alleviates GSDMD‐mediated microglia pyroptosis in spinal cord injury through PI3K/AKT/Foxo1 signaling

Xu, Shun; Wang, Jin; Zhong, Junjie; Shao, Minghao; Jiang, Jianyuan; Song, Jian; Zhu, Wei; Zhang, Fan; Xu, Haocheng; Xu, Guangyu; Zhang, Yuxuan; Ma, Xiaosheng; Lyu, Feizhou

doi:10.1002/ctm2.269

Cited by 153 publications

(107 citation statements)

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“…Thus, secondary injury prevention and intervention are considered promising treatments for SCI [ 8 ]. Among the mentioned pathophysiologic events in secondary injury, cell death and inflammation are considered to be two critical targets for SCI treatment [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

GDF‐11 Protects the Traumatically Injured Spinal Cord by Suppressing Pyroptosis and Necroptosis via TFE3‐Mediated Autophagy Augmentation

et al. 2021

Oxidative Medicine and Cellular Longevity

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Spinal cord injury (SCI) refers to a major worldwide cause of accidental death and disability. However, the complexity of the pathophysiological mechanism can result in less-effective clinical treatment. Growth differentiation factor 11 (GDF-11), an antiageing factor, was reported to affect the development of neurogenesis and exert a neuroprotective effect after cerebral ischaemic injury. The present work is aimed at investigating the influence of GDF-11 on functional recovery following SCI, in addition to the potential mechanisms involved. We employed a mouse model of spinal cord contusion injury and assessed functional outcomes via the Basso Mouse Scale and footprint analysis following SCI. Using western blot assays and immunofluorescence, we analysed the levels of pyroptosis, autophagy, necroptosis, and molecules related to the AMPK-TRPML1-calcineurin signalling pathway. The results showed that GDF-11 noticeably optimized function-related recovery, increased autophagy, inhibited pyroptosis, and alleviated necroptosis following SCI. Furthermore, the conducive influences exerted by GDF-11 were reversed with the application of 3-methyladenine (3MA), an autophagy suppressor, indicating that autophagy critically impacted the therapeutically related benefits of GDF-11 on recovery after SCI. In the mechanistic study described herein, GDF-11 stimulated autophagy improvement and subsequently inhibited pyroptosis and necroptosis, which were suggested to be mediated by TFE3; this effect resulted from the activity of TFE3 through the AMPK-TRPML1-calcineurin signalling cascade. Together, GDF-11 protects the injured spinal cord by suppressing pyroptosis and necroptosis via TFE3-mediated autophagy augmentation and is a potential agent for SCI therapy.

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Section: Introductionmentioning

confidence: 99%

GDF‐11 Protects the Traumatically Injured Spinal Cord by Suppressing Pyroptosis and Necroptosis via TFE3‐Mediated Autophagy Augmentation

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…Besides, the microglia pyroptosis has also emerged as another important resource of neuroin ammation in SCI. In our previous studies, we have identi ed the crucial role of microglia pyroptosis in SCI [15]. It is a novel kind of in ammatory programmed cell death characterized by cell swelling and lysis, leading to the secretion of proin ammatory cytokines (including IL-1β, IL-18 and TNF-α).…”

Section: Discussionmentioning

confidence: 99%

“…Recent researches have shown that NLRP3-mediated pyroptosis plays crucial roles in various diseases including intestinal diseases [10], cardiovascular diseases [11,12], neurological disease [13] as well as the age-related diseases [14]. Importantly, some researchers and we previously reported that NLRP3 in ammasome-mediated pyroptosis is also involved in SCI and the inhibition of pyroptosis may be one of the potential treatment targets for SCI [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Melatonin Alleviates Microglia-Mediated Neuroinflammation By Suppressing NLRP3 Inflammasome-Mediated Pyroptosis Via ROS/mtDNA/STING Pathway After Spinal Cord Injury

Wang¹,

Yang²,

Zhang³

et al. 2021

Preprint

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BackgroundMicroglia pyroptosis-induced neuroinflammation has been one of the potential treatment targets for spinal cord injury (SCI). And melatonin is reported to have anti-neuroinflammation effect on SCI, but the underlying mechanism is largely unexplored. In addition, the potential regulatory role of stimulator of interferon genes (STING) mediated innate immune response in the SCI-induced neuroinflammation also remains unknown. The aim of this study is to identify the potential molecular mechanism of the anti-neuroinflammation effect of melatonin in SCI mice and to explore whether STING-mediated signal pathway is involved in this pharmacological process. MethodsIn vivo, the C57BL/6 female mice underwent SCI injury or Sham surgery (laminectomy alone). Melatonin and selective STING antagonist C-176 were administered intraperitoneally after injury in the SCI group once a day for 3 or 28 consecutive days for different experiments. The BMS score system was adopted to assess the motor function of mice. In vitro, the Lipopolysaccharide (LPS)/ATP was combinedly used to induce cell pyroptosis in BV2 microglia and the adenovirus was used to overexpress STING. A series of molecular experiments including Western blot (WB), quantitative real-time polymerase chain reaction (RT-qPCR), enzyme linked immunosorbent assay (ELISA) and immunofluorescence (IF) were performed in vivo and in vitro. ResultsOur results showed that melatonin effectively suppressed NLRP3 inflammasome-induced pyroptosis and STING-mediated pathway after SCI. In addition, C-176 also alleviated the NLRP3 inflammasome-mediated pyroptosis and promoted functional recovery in vivo. In vitro, we also found that melatonin abrogated NLRP3 inflammasome activation in LPS/ATP-induced BV2 cells, while overexpression of STING reversed the anti-pyroptotic role of melatonin. Subsequent results together indicated that the role of melatonin on STING-dependent NLRP3 inflammasome activation may be mediated by decreasing ROS production and cytosolic mtDNA release. ConclusionThis study preliminarily demonstrated that melatonin exerts its anti-neuroinflammation role on SCI by alleviating the NLRP3 inflammasome-mediated pyroptosis, which was mediated by blocking the ROS/mtDNA/STING pathway. It provides us a better understanding of the pathological mechanism after SCI and offer experiment evidence to promote the use of melatonin for SCI.

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“…During NLRP3 inflammasome activation, ASC and NLRP3 oligomerization are acritical steps for the subsequent caspase‐1 activation. 3 , 4 , 5 , 6 NR4A1 deficiency aggravates Nigericin‐induced amounts of ASC specks, and the interaction between NLRP3 and ASC in BMDMs (Figure 2F and Figure S4 ). Meanwhile, overexpression of NR4A1 inhibits canonical and non‐canonical NLRP3 inflammasome activation in THP‐1 and BMDMs (Figure S2D,G and Figure S3E,F ).…”

Section: Figurementioning

confidence: 98%

NR4A1 suppresses pyroptosis by transcriptionally inhibiting NLRP3 and IL‐1β and co‐localizing with NLRP3 in trans‐Golgi to alleviate pathogenic bacteria‐induced colitis

Deng

Yang

Cui

et al. 2021

Clinical & Translational Med

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Dear Editor,We present an effective target to treat colitis would be achieved through the transcriptional regulation and trans-Golgi translocation of NR4A1, so as to inhibit NLR family, pyrin domain containing 3 (NLRP3) inflammasome. Inflammatory bowel disease (IBD) is a chronic and intractable digestive tract inflammatory disease that affects the millions of people; blocking immune responses and inflammatory cytokines have become effective strategies for treating colitis. NR4A1 (also known as TR3, NGFIB or Nur77), a member of the nuclear receptor NR4A family, exerts a protective role in colitis, 1,2 however, its effect and mechanism on pyroptosis or NLRP3 inflammasome is still unclear.In current study, NR4A1 expression is significantly increased in colon tissues from C. rodentium (Citrobacter rodentium)-induced mice colitis (Figure 1A,B). And NR4A1 deficiency increases C. rodentium-induced mortality, weight loss, colon shorten, colon mucosal damage and the colonization of C. rodentium (Figure 1C-F and Figure S1B-F). For pyroptosis and inflammasome, NR4A1 deficiency increases the level of lactate dehydrogenase (LDH), interleukin-1β (IL-1β), IL-18, caspase-1 p20 and the cleavage of gasdermin D (GSDMD) in serum or colon (Figure 1G-L and Figure S1G,H). These results indicated that NR4A1 deficiency exacerbates inflammasome activation and pyroptosis in vivo.To investigate the role of NR4A1 in inflammasome activation, we isolated bone marrow-derived macrophages (BMDMs) from WT mice and NR4A1 −/− mice. For canonical inflammasome, the results showed that NR4A1 only inhibits NLRP3 inflammasome, without affecting NLRC4 or AIM2 inflammasome (Figure S2A,B). NR4A1 expression is increased after the first and the second stimulation of NLRP3 inflammasome (Figure S2C). And NR4A1 deficiency augments Nigericin-induced LDH, IL-1β, IL-18 and caspase-1 cleavage (Figure 2A-E and Fig-This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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CD73 alleviates GSDMD‐mediated microglia pyroptosis in spinal cord injury through PI3K/AKT/Foxo1 signaling

Cited by 153 publications

References 69 publications

GDF‐11 Protects the Traumatically Injured Spinal Cord by Suppressing Pyroptosis and Necroptosis via TFE3‐Mediated Autophagy Augmentation

GDF‐11 Protects the Traumatically Injured Spinal Cord by Suppressing Pyroptosis and Necroptosis via TFE3‐Mediated Autophagy Augmentation

Melatonin Alleviates Microglia-Mediated Neuroinflammation By Suppressing NLRP3 Inflammasome-Mediated Pyroptosis Via ROS/mtDNA/STING Pathway After Spinal Cord Injury

NR4A1 suppresses pyroptosis by transcriptionally inhibiting NLRP3 and IL‐1β and co‐localizing with NLRP3 in trans‐Golgi to alleviate pathogenic bacteria‐induced colitis

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