Role of Myeloid Lineage Cell Autophagy in Ischemic Brain Injury

Kotoda, Masakazu; Furukawa, Hajime; Miyamoto, Takeshi; Korai, Masaaki; Shikata, Fumiaki; Kuwabara, Atsushi; Xiong, Xiaoxing; Rutledge, Caleb; Giffard, Rona G.; Hashimoto, Tomoki

doi:10.1161/strokeaha.117.018637

Cited by 25 publications

(20 citation statements)

References 67 publications

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“…A population-based retrospective cohort study revealed that 18% of patients with central nervous system (CNS) infections developed CMHs within one year after the initial infection, 47 times greater than non-CNS infection controls [34]. Infections complicating cerebrovascular accidents have been extensively investigated [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54]. However, the role of CMHs complicating infections [55][56][57][58], in particular, acute infections, has been poorly explored [34,[59][60][61].…”

Section: Introductionmentioning

confidence: 99%

Annexin A2 depletion exacerbates the intracerebral microhemorrhage induced by acute rickettsia and Ebola virus infections

Chang

Drelich

et al. 2020

PLoS Negl Trop Dis

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Intracerebral microhemorrhages (CMHs) are small foci of hemorrhages in the cerebrum. Acute infections induced by some intracellular pathogens, including rickettsia, can result in CMHs. Annexin a2 (ANXA2) has been documented to play a functional role during intracellular bacterial adhesion. Here we report that ANXA2-knockout (KO) mice are more susceptible to CMHs in response to rickettsia and Ebola virus infections, suggesting an essential role of ANXA2 in protecting vascular integrity during these intracellular pathogen infections. Proteomic analysis via mass spectrometry of whole brain lysates and brain-derived endosomes from ANXA2-KO and wild-type (WT) mice post-infection with R. australis revealed that a variety of significant proteins were differentially expressed, and the follow-up function enrichment analysis had identified several relevant cell-cell junction functions. Immunohistology study confirmed that both infected WT and infected ANXA2-KO mice were subjected to adherens junctional protein (VE-cadherin) damages. However, key blood-brain barrier (BBB) components, tight junctional proteins ZO-1 and occludin, were disorganized in the brains from R. australis-infected ANXA2-KO mice, but not those of infected WT mice. Similar ANXA2-KO dependent CMHs and fragments of ZO-1 and occludin were also observed in Ebola virus-infected ANXA2-KO mice, but not found in infected WT mice. Overall, our study revealed a novel role of ANXA2 in the formation of CMHs during R. australis and Ebola virus infections; and the underlying mechanism is relevant to the role of ANXA2-regulated tight junctions and its role in stabilizing the BBB in these deadly infections.

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Section: Introductionmentioning

confidence: 99%

Annexin A2 depletion exacerbates the intracerebral microhemorrhage induced by acute rickettsia and Ebola virus infections

Chang

Drelich

et al. 2020

PLoS Negl Trop Dis

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“…However, the down-regulation of hsp60 observed by the authors may not assess the occurrence of a pre-activation of autophagy by ischemic preconditioning, in order to boost further endogenous defense mechanisms [30]. Furthermore, although CRMP2 is particularly involved in autophagy, as it exerts a role in the efficient traffic of LC3-II containing autophagic vesicles, its involvement cannot be fully explained with the action exerted by quercetin on autophagy [21].…”

mentioning

confidence: 87%

“…We observed that the cross-talk between glial cells and neurons is of the utmost importance, during brain injury. A recent paper reported that in the ischemic stroke, inflammatory cells in the glia play a fundamental role in the exacerbation of ischemia causing neuronal cell apoptosis, if cells of myeloid lineage lack of an autophagic response [21]. Autophagy in this case has a protective role in preventing ischemia-induced damage of neuronal cells and interestingly quercetin, as many other polyphenols, is also an autophagy inducer [22].…”

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confidence: 99%

Quercetin Might Promote Autophagy in a Middle Cerebral Artery Occlusion-Mediated Ischemia Model: Comments on Fawad-Ali Shah et al.

2018

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The recent paper by Fawad-Ali Shah on this journal describes the role of the flavonoid quercetin in a cerebral ischemia model induced in adult Sprague-Dawley male rats by middle cerebral artery occlusion (MCAO) [1]. The authors reported that quercetin in MCAO-induced ischemia modulated the expression of the enzymes isocitrate dehydrogenase [NAD + ] (which is present in two isoforms, EC. 1.1.1.41 and EC 1.1.1.42), adenosyl-homocysteinase (EC, 3.3.1.1), pyruvate kinase (EC 2.7.1.40), ubiquitin carboxy terminal hydrolase L1 (EC, 3.1.2.15), besides to the proteins heat shock protein 60 (hsp60) and collapsin response mediator protein 2 (CRMP2) [1]. Actually, many further important proteins are upregulated (and some of them down-regulated) by quercetin in the reported MCAO model [1]. Following Fawad-Ali Shah et al.'s paper, we hypothesized that the up-or down-regulation of the many specific proteins by quercetin might deal with the occurrence of an autophagic mechanism, directly or indirectly promoted by the flavonoid itself in the MCAO-induced ischemia [1]. Autophagy is a regular, physiological process adopted by cells to disassembly dysfuncional, damaged or unnecessary components, including organelles such as mitochondria (mitophagy). It usually involves a cascade of events starting with the phosphorylation of beclin-1 (the mammalian homologue of Atg6) [2]. The cell self-digesting mechanism that is responsible for the removal of long-lived proteins * Salvatore Chirumbolo

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“…In response to an injury, the NLRP3 inflammasome can be regulated by autophagy, an intracellular homeostatic recycling process that eliminates damaged organelles and toxic agents, including inflammasomes [28]. Emerging research shows that autophagy modulates microglial inflammatory response via NLRP3 degradation [29], and autophagy impairment worsens neuroinflammation [30,31] and ischemic injury [32]. The pharmacological induction of autophagy inhibits inflammation and improves outcome in rodent models of cardiac arrest [33,34].…”

Section: Introductionmentioning

confidence: 99%

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

Espinosa‐García

Atif

Yousuf

et al. 2020

IJMS

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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.

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Role of Myeloid Lineage Cell Autophagy in Ischemic Brain Injury

Abstract: These data suggest that the lack of myeloid cell autophagy aggravates secondary injury by augmenting and prolonging inflammation after ischemic stroke without affecting the initial injury.

Cited by 25 publications

References 67 publications

Annexin A2 depletion exacerbates the intracerebral microhemorrhage induced by acute rickettsia and Ebola virus infections

Annexin A2 depletion exacerbates the intracerebral microhemorrhage induced by acute rickettsia and Ebola virus infections

Quercetin Might Promote Autophagy in a Middle Cerebral Artery Occlusion-Mediated Ischemia Model: Comments on Fawad-Ali Shah et al.

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

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