miR-194 ameliorates hepatic ischemia/reperfusion injury via targeting PHLDA1 in a TRAF6-dependent manner

Luo, Yunhai; Huang, Zuotian; Zong, Kezhen; Cao, Zhen-Rui; Peng, Dadi; Zhou, Baoyong; Shen, Ai; Yan, Ping; Wu, Zhongjun

doi:10.1016/j.intimp.2021.107604

Cited by 22 publications

(24 citation statements)

References 35 publications

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“…found that PHLDA1 directly interacted with TRAF6 and augmented K63-linked ubiquitination to activate the NF-κB signaling pathway, which in turn promoted the production of LPS-induced proinflammatory cytokines (TNF-α and IL-1β) and associated genes (iNOS and COX-2) in microglia cells. These findings indicated that PHLDA1 may be a potent regulator for neuroinflammation ( 30 , 31 ). It was reported that PHLDA1 upregulation was dependent of RAW264.7 cell proliferation and cell cycle progression induced by LPS ( 32 ).…”

Section: Discussionmentioning

confidence: 91%

PHLDA1 Suppresses TLR4-Triggered Proinflammatory Cytokine Production by Interaction With Tollip

et al. 2022

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Pleckstrin homology-like domain, family A, member 1 (PHLDA1) has been reported to be expressed in many mammalian tissues and cells. However, the functions and exact mechanisms of PHLDA1 remain unclear. In this study, we found that PHLDA1 expression was significantly altered in macrophages after exposure to lipopolysaccharide (LPS) in vitro, suggesting that PHLDA1 may be involved in the regulation of TLR4 signaling pathway activated by LPS. PHLDA1 attenuated the production of LPS-stimulated proinflammatory cytokines (TNF-α, IL-6, and IL-1β). Further research showed that the phosphorylation levels of some important signal molecules in TLR4/MyD88-mediated MAPK and NF-κB signaling pathways were reduced by PHLDA1, which in turn impaired the transcription factors NF-κB and AP1 nuclear translocation and their responsive element activities. Furthermore, we found that PHLDA1 repressed LPS-induced proinflammatory cytokine production via binding to Tollip which restrained TLR4 signaling pathway. A mouse model of endotoxemia was established to confirm the above similar results. In brief, our findings demonstrate that PHLDA1 is a negative regulator of LPS-induced proinflammatory cytokine production by Tollip, suggesting that PHLDA1 plays an anti-inflammatory role through inhibiting the TLR4/MyD88 signaling pathway with the help of Tollip. PHLDA1 may be a novel therapeutic target in treating endotoxemia.

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Section: Discussionmentioning

confidence: 91%

PHLDA1 Suppresses TLR4-Triggered Proinflammatory Cytokine Production by Interaction With Tollip

et al. 2022

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“…miR-194 was down regulated in hepatic IRI, resulting in the upregulation of its target, pleckstrin homology-like domain family member 1 (PHLDA1) [53]. PHLDA1 activates TNF receptor-associated factor 6 (TRAF6), which exaggerates stress responses and inflammation during IRI through mitogen-activated protein (MAPK) initiation [53]. Impaired liver function was evident when PHLDA1 was overexpressed due to an increase in cytokines and chemokines [53].…”

Section: Mir-194mentioning

confidence: 99%

“…PHLDA1 activates TNF receptor-associated factor 6 (TRAF6), which exaggerates stress responses and inflammation during IRI through mitogen-activated protein (MAPK) initiation [53]. Impaired liver function was evident when PHLDA1 was overexpressed due to an increase in cytokines and chemokines [53]. miR-194 mimic and miR-194 antagomir were used to compare results to evaluate the mechanisms of the miR-194/PHLDA1 axis [53].…”

Section: Mir-194mentioning

confidence: 99%

“…Impaired liver function was evident when PHLDA1 was overexpressed due to an increase in cytokines and chemokines [53]. miR-194 mimic and miR-194 antagomir were used to compare results to evaluate the mechanisms of the miR-194/PHLDA1 axis [53]. When miR-194 was overexpressed, ALT and AST levels were lower, along with the lower expression of TNF-α, IL-6, IL-1β, and CXCL-10 [53].…”

Section: Mir-194mentioning

confidence: 99%

“…miR-194 mimic and miR-194 antagomir were used to compare results to evaluate the mechanisms of the miR-194/PHLDA1 axis [53]. When miR-194 was overexpressed, ALT and AST levels were lower, along with the lower expression of TNF-α, IL-6, IL-1β, and CXCL-10 [53]. Targeting PHLDA1 through the overexpression of miR-194 has potential as a therapeutic agent to ameliorate liver damage.…”

Section: Mir-194mentioning

confidence: 99%

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MicroRNAs: Novel Targets in Hepatic Ischemia–Reperfusion Injury

et al. 2022

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Hepatic ischemia–reperfusion injury (IRI) is one of the main factors for early allograft dysfunction (EAD), which may lead to graft rejection, graft loss, or shortened graft life in liver transplantation. Hepatic IRI appears to be inevitable during the majority of liver procurement and transportation of donor organs, resulting in a cascade of biological changes. The activation of signaling pathways during IRI results in the up- and downregulation of genes and microRNAs (miRNAs). miRNAs are ~21 nucleotides in length and well-characterized for their role in gene regulations; they have recently been used for therapeutic approaches in addition to their role as biomarkers for many diseases. miRNAs that are associated with hepatic IRI in in vitro and in vivo animal models are comprehensively summarized in this review. In those studies, the manipulation of miRNAs has been shown for the inhibition of aggravated immune response, reduction of apoptosis, stimulation of tissue repair, and enhancement of cell recovery to attenuate liver damage. Therefore, the utilization of liver-specific miRNA holds great potential as a therapeutic agent to improve early allograft dysfunction, hepatic injury, and patient outcome.

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Rosiglitazone attenuates Acute Kidney Injury from hepatic ischemia–reperfusion in mice by inhibiting arachidonic acid metabolism through the PPAR-γ/NF-κB pathway

Qin,

Tan,

et al. 2024

Inflamm. Res.

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miR-194 ameliorates hepatic ischemia/reperfusion injury via targeting PHLDA1 in a TRAF6-dependent manner

Cited by 22 publications

References 35 publications

PHLDA1 Suppresses TLR4-Triggered Proinflammatory Cytokine Production by Interaction With Tollip

PHLDA1 Suppresses TLR4-Triggered Proinflammatory Cytokine Production by Interaction With Tollip

MicroRNAs: Novel Targets in Hepatic Ischemia–Reperfusion Injury

Rosiglitazone attenuates Acute Kidney Injury from hepatic ischemia–reperfusion in mice by inhibiting arachidonic acid metabolism through the PPAR-γ/NF-κB pathway

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