Thymosin β4 inhibits microglia activation through microRNA 146a in neonatal rats following hypoxia injury

Zhou, Tian; Huang, Yanxia; Song, Jianwen; Ma, Qiao-mei

doi:10.1097/wnr.0000000000000463

Cited by 21 publications

(28 citation statements)

References 25 publications

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“…Several lines of evidence support that miR-146a serves as a negative feedback regulator of the TLR-mediated NF-κB activity by targeting TRAF6 and IRAK1 in myeloid immune cells and microglia (Boldin et al , 2011; Saba et al , 2012; Taganov et al , 2006). Notably, a recent study has shown that thymosin β4, a G-actin-sequestering molecule with anti-inflammatory features, inhibits microglia activation and neuroinflammation in neonatal rats following HI insult, which is associated with upregulated expression of miR-146a (Zhou et al , 2015). Another CNS enriched miRNA, miR-124, is down-regulated in the brain of rats subjected to the transient focal ischemia (Zhu et al , 2014).…”

Section: Mirna Modulation In Neuroinflammationmentioning

confidence: 99%

Brain-immune interactions in perinatal hypoxic-ischemic brain injury

Concepcion

Meng

et al. 2017

Progress in Neurobiology

187

189

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Perinatal hypoxia-ischemia remains the primary cause of acute neonatal brain injury, leading to a high mortality rate and long-term neurological deficits, such as behavioral, social, attentional, cognitive and functional motor deficits. An ever-increasing body of evidence shows that the immune response to acute cerebral hypoxia-ischemia is a major contributor to the pathophysiology of neonatal brain injury. Hypoxia-ischemia provokes an intravascular inflammatory cascade that is further augmented by the activation of resident immune cells and the cerebral infiltration of peripheral immune cells response to cellular damages in the brain parenchyma. This prolonged and/or inappropriate neuroinflammation leads to secondary brain tissue injury. Yet, the long-term effects of immune activation, especially the adaptive immune response, on the hypoxic-ischemic brain still remain unclear. The focus of this review is to summarize recent advances in the understanding of post-hypoxic-ischemic neuroinflammation triggered by the innate and adaptive immune responses and to discuss how these mechanisms modulate the brain vulnerability to injury. A greater understanding of the reciprocal interactions between the hypoxic-ischemic brain and the immune system will open new avenues for potential immunomodulatory therapy in the treatment of neonatal brain injury.

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Section: Mirna Modulation In Neuroinflammationmentioning

confidence: 99%

Brain-immune interactions in perinatal hypoxic-ischemic brain injury

Concepcion

Meng

et al. 2017

Progress in Neurobiology

187

189

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“…The microglia are the most important inflammatory cells in the CNS; inflammation mediated by activated microglia leads to pathologic changes in most CNS diseases and injury [13][14][15]. Endogenous Tβ4 in the CNS is reported to be expressed mainly in microglia and direct evidence has shown that Tβ4 may inhibit inflammatory factor expression in microglia after hypoxia [12]. Furthermore, systemic administration of Tβ4 is safe and well-tolerated by humans and animals, including neonatal rats [3].…”

Section: Introductionmentioning

confidence: 99%

“…Double immunofluorescence was performed as previously described [12]. Coronal sections of brain were stained with Iba-1 and Tβ4 antibodies (Abcam, Cambridge, UK).…”

Section: Double Immunofluorescencementioning

confidence: 99%

“…Multiple studies have indicated that Tβ4 protein may promote tissue regeneration in multiple processes including corneal, epidermal, and cardiac wound healing, and is also effective in inflammatory diseases including severe acute pancreatitis and bleomycininduced lung fibrosis [8]. In CNS, Tβ4 has been reported to be neuroprotective in rodents with experimental autoimmune encephalomyelitis, stroke and traumatic brain injury (TBI), and also neonatal rats following hypoxia brain injury [9][10][11][12]. The effects of Tβ4 in these diseases are partly through inhibition of inflammation.…”

Section: Introductionmentioning

confidence: 99%

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Function of Thymosin Beta-4 in Ethanol-Induced Microglial Activation

Zhang¹,

Wu²,

Zeng³

et al. 2016

Cell Physiol Biochem

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Background/Aims: Neuroinflammation mediated by activated microglia may play a pivotal role in a variety of central nervous system (CNS) pathologic conditions, including ethanolinduced neurotoxicity. The purpose of this study was to investigate the function of Tβ4 in ethanol-induced microglia activation. Methods: Quantitative real-time PCR was conducted to assess the expression of Tβ4 and miR-339-5p. Western blot analysis was used to measure the expression of Tβ4, phosphorylated p38, ERK, JNK, Akt, and NF-κB p65. The concentration of TNF-α and IL-1β was determined using ELISA. NO concentration was measured using a nitric oxide colorimetric BioAssay Kit. Double immunofluorescence was performed to determine Tβ4 expression, in order to assess microglial activation in neonatal mouse FASD model. Results: Increased Tβ4 expression was observed in ethanol treated microglia. Knockdown of Tβ4 enhanced ethanol-induced inflammatory mediators tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) and nitric oxide (NO) in BV-2 cells was performed. Exogenous Tβ4 treatment significantly inhibited expression and secretion of these inflammatory mediators. Tβ4 treatment attenuated p38, ERK MAPKs, and nuclear factor-kappa B (NF-κB) pathway activation, and enhanced miR-339-5p expression induced by ethanol exposure in microglia. A neonatal mouse fetal alcohol spectrum disorders (FASD) model showed that Tβ4 expression in the microglia of the hippocampus was markedly enhanced, while Tβ4 treatment effectively blocked the ethanol-induced increase in inflammatory mediators, to the level expressed in vehicle-treated control animals. Conclusion: This study is the first to demonstrate the function of Tβ4 in ethanol-induced microglia activation, thus contributing to a more robust understanding of the role of Tβ4 treatment in CNS disease.

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“…For example, Tβ4 inhibited expression of inflammatory mediators in endotoxin-induced septic shock (37). It also appeared to have an anti-inflammatory effect in neonatal rats by inhibiting microglia activation through microRNA146a (38), and it inhibited the activation of NF-κB in TNF-α-stimulated cells (39). Thus, Tβ4 was regarded as an agent of anti-inflammatory activity (40), while another report concluded that Tβ4 stimulates proinflammatory cytokine secretion in human pancreatic cancer cells (41).…”

Section: Thymosin β4 and Rheumatoid Arthritismentioning

confidence: 99%

Thymosin β4 in rheumatoid arthritis: Friend or foe

Kim

Yang

2017

Biomedical Reports

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Abstract. Rheumatoid arthritis (RA) has characteristic pannus tissues, which show tumor-like growth of the synovium through chronic joint inflammation. The synovium is highly penetrated by various immune cells, and the synovial lining becomes hyperplastic due to increased numbers of macrophage-like and fibroblast-like synoviocytes. Thus, a resultant hypoxic condition stimulates the expression of inflammation-related genes in various cells, in particular, vascular endothelial growth factor. Thymosin β4 (Tβ4), a 5-kDa protein, is known to play a significant role in various biological activities, such as actin sequestering, cell motility, migration, inflammation, and damage repair. Recent studies have provided evidence that Tβ4 may have a role in RA pathogenesis. The Tβ4 level has been shown to increase significantly in the joint fluid and serum of RA patients. However, whether Tβ4 stimulates or inhibits activation of RA immune responses remains to be determined. In the present study, we discuss the logical and clinical justifications for Tβ4 as a potential target for RA therapeutics. IntroductionCytokines control an extensive range of inflammatory progressions that are associated with the pathogenesis of rheumatoid arthritis (RA). In arthritic joints, pro-inflammatory activities lead to the induction of autoimmunity, chronic inflammation, and, ultimately, joint damage (1). A better understanding of these pathogenic mechanisms has enabled the development of therapeutic agents to inhibit cytokine actions, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1, and IL-6, which have greatly contributed to the management of RA patients (2,3). Biological therapies have contributed innovative improvements to RA treatment (4). However, despite these improvements, 30-50% of RA patients who are non-responders to disease-modifying antirheumatic drugs (DMARDs) fail to respond to treatment with biologic agents (5). Furthermore, radiographic joint damage can proceed even when clinical disease reduction is achieved by biologic agents (6).These results indicate that the inhibition of cytokine networks may not be satisfactory to suppress RA progression. Thus, there is a need for new therapeutic agents to target new molecules, which encouraged us to redirect our efforts to screen other therapeutic targets from joint synovial fluids of RA patients. Recently, we observed that the level of thymosin β4 (Tβ4), which has many biological roles, was significantly increased in the serum and joint fluids of RA patients (7,8). This review aims to discuss the current understanding of the potential role of Tβ4 in RA pathogenesis while addressing current knowledge regarding the association between Tβ4 and arthritic joints for RA management. Rheumatoid arthritisRA is an autoimmune inflammatory disease whose pathogenic mechanisms remain elusive. RA pathogenesis is attributed to a complex interaction between genetic and environmental factors (7). The class II major histocompatibility complex molecules HLA-DR1 and HLA-DR4 are regarded as major...

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Thymosin β4 inhibits microglia activation through microRNA 146a in neonatal rats following hypoxia injury

Cited by 21 publications

References 25 publications

Brain-immune interactions in perinatal hypoxic-ischemic brain injury

Brain-immune interactions in perinatal hypoxic-ischemic brain injury

Function of Thymosin Beta-4 in Ethanol-Induced Microglial Activation

Thymosin β4 in rheumatoid arthritis: Friend or foe

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