MiR-146a upregulates FOXP3 and suppresses inflammation by targeting HIPK3/STAT3 in allergic conjunctivitis

Guo, Hui; Zhang, Yongxin; Liao, Zifang; Zhan, Wenzhu; Wang, Yuan; Peng, Yun; Yang, Meng‐Yin; Ma, Xudai; Yin, Guogan; Ye, Lin

doi:10.21037/atm-22-982

Cited by 3 publications

(3 citation statements)

References 46 publications

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“…The combination of suppression of innate, adaptive immune response genes and upregulation of T reg from the microRNA 146a administration could have abrogated EAU. microRNA146a was also reported to suppress exacerbation of inflammation in allergic conjunctivitis by upregulation of FOXP3 and downregulation of pSTAT3 thus demonstrating a protective mechanism (62). Transgenic mice with altered miRNA expression have also been used successfully to study miRNA function, and have been designed to target miRNA expression at certain stages during development, as well as in a tissue-or cell type-specific manner (63,64).…”

Section: Discussionmentioning

confidence: 99%

microRNA 146a ameliorates retinal damage in experimental autoimmune uveitis

Saraswathy

Rao

2023

Front. Ophthalmol.

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IntroductionUveitis and related intraocular inflammations are a major cause of blindness due to retinal damage caused by degeneration and loss of the photoreceptor cells. In mouse experimental autoimmune uveitis (EAU) previously we have shown mitochondrial oxidative stress with marked upregulation of αA crystallin in the inner segments of the photoreceptors. Furthermore, αA crystallin treatment prevented photoreceptor mitochondrial oxidative stress by suppressing innate and adaptive immunity in EAU.MethodsSince these immune processes are modulated by microRNAs, in this study we investigated (a) modulation of microRNAs during development of EAU by αA crystallin administration and (b) microRNA therapeutic intervention.ResultsFew microRNAs were significantly upregulated in EAU mice with intravenous injection of αA crystallin and among these, computational bioinformatic analysis revealed that the upregulated microRNA 146a targets the innate and adaptive immune responses. In EAU, intravenous as well as intravitreal administration of this microRNA prevented inflammatory cell infiltration in uvea and retina and preserved photoreceptor cells.DiscussionThis protective function suggests that microRNA146a can be a novel therapeutic agent in preventing retinal damage in uveitis.

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Section: Discussionmentioning

confidence: 99%

microRNA 146a ameliorates retinal damage in experimental autoimmune uveitis

Saraswathy

Rao

2023

Front. Ophthalmol.

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“…Ye and Steinle ( 57 ) reported that miR-146a inhibited inflammation and apoptosis as a potential molecular treatment in the diabetic retina by participating in inhibiting the IL-6-related JAK/STAT3 pathway. Furthermore, miR-146a was reported to inhibit the pro-inflammatory function of STAT3 by targeting homeodomain-interacting protein kinases 3 ( 58 ). Downregulation of miR-146a increased the levels of phosphorylated STAT3 protein ( 59 ), consistent with the result that STAT3 had significantly higher activity in miR-146a-deficient mice ( 60 ).…”

Section: Mir-146a and Inflammationmentioning

confidence: 99%

“…However, one study reported that in patients with allergic rhinitis, miR-146a elevated Treg functions and differentiation via targeting STAT5b ( 79 ). Guo et al ( 58 ) indicated that miR-146a mediated Treg-cell differentiation via upregulating FOXP3 expression. IL-6-driven STAT3 signaling is required for the nuclear retinoic acid receptor-related orphan receptor-γ-t function involved in Th17-cell differentiation.…”

Section: Mir-146a and Inflammationmentioning

confidence: 99%

Mechanisms and application strategies of miRNA‑146a regulating inflammation and fibrosis at molecular and cellular levels (Review)

2022

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In the progression of various diseases, inflammation has a critical role. Chronic persistent inflammation is a pivotal trigger of fibrosis. Several microRNAs (miRNAs) participate in inflammation and fibrosis. In recent years, it has been proved that miRNAs are a critical link in physiological and pathological processes. Among them, the miRNA miR-146a has a pivotal role in the immune system and acquired immunity, making it one of the most studied miRNAs. Due to its essential roles at the molecular and cellular levels, it has broad application prospects in precision medicine. The present comprehensive review focused on the mechanisms of miR-146a and its application strategies in inflammation and fibrosis, discussing its therapeutic potential. The main signaling pathways through which miR-146a regulates inflammation and fibrosis and their relationships were covered. Furthermore, the functions and effects of miR-146a in specific cells, which may join in the process of inflammation and fibrosis, were outlined. Application strategies were also summarized according to recent studies based on these mechanisms. Contents 1. Introduction 2. Location and transcription regulation of miR-146a 3. miR-146a and inflammation 4. miR-146a and fibrosis 5. Application strategies 6. Conclusions and perspectives

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KSFinder—a knowledge graph model for link prediction of novel phosphorylated substrates of kinases

Anandakrishnan,

Ross,

Chen

et al. 2023

PeerJ

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Background Aberrant protein kinase regulation leading to abnormal substrate phosphorylation is associated with several human diseases. Despite the promise of therapies targeting kinases, many human kinases remain understudied. Most existing computational tools predicting phosphorylation cover less than 50% of known human kinases. They utilize local feature selection based on protein sequences, motifs, domains, structures, and/or functions, and do not consider the heterogeneous relationships of the proteins. In this work, we present KSFinder, a tool that predicts kinase-substrate links by capturing the inherent association of proteins in a network comprising 85% of the known human kinases. We also postulate the potential role of two understudied kinases based on their substrate predictions from KSFinder. Methods KSFinder learns the semantic relationships in a phosphoproteome knowledge graph using a knowledge graph embedding algorithm and represents the nodes in low-dimensional vectors. A multilayer perceptron (MLP) classifier is trained to discern kinase-substrate links using the embedded vectors. KSFinder uses a strategic negative generation approach that eliminates biases in entity representation and combines data from experimentally validated non-interacting protein pairs, proteins from different subcellular locations, and random sampling. We assess KSFinder’s generalization capability on four different datasets and compare its performance with other state-of-the-art prediction models. We employ KSFinder to predict substrates of 68 “dark” kinases considered understudied by the Illuminating the Druggable Genome program and use our text-mining tool, RLIMS-P along with manual curation, to search for literature evidence for the predictions. In a case study, we performed functional enrichment analysis for two dark kinases - HIPK3 and CAMKK1 using their predicted substrates. Results KSFinder shows improved performance over other kinase-substrate prediction models and generalized prediction ability on different datasets. We identified literature evidence for 17 novel predictions involving an understudied kinase. All of these 17 predictions had a probability score ≥0.7 (nine at >0.9, six at 0.8–0.9, and two at 0.7–0.8). The evaluation of 93,593 negative predictions (probability ≤0.3) identified four false negatives. The top enriched biological processes of HIPK3 substrates relate to the regulation of extracellular matrix and epigenetic gene expression, while CAMKK1 substrates include lipid storage regulation and glucose homeostasis. Conclusions KSFinder outperforms the current kinase-substrate prediction tools with higher kinase coverage. The strategically developed negatives provide a superior generalization ability for KSFinder. We predicted substrates of 432 kinases, 68 of which are understudied, and hypothesized the potential functions of two dark kinases using their predicted substrates.

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MiR-146a upregulates FOXP3 and suppresses inflammation by targeting HIPK3/STAT3 in allergic conjunctivitis

Cited by 3 publications

References 46 publications

microRNA 146a ameliorates retinal damage in experimental autoimmune uveitis

microRNA 146a ameliorates retinal damage in experimental autoimmune uveitis

Mechanisms and application strategies of miRNA‑146a regulating inflammation and fibrosis at molecular and cellular levels (Review)

KSFinder—a knowledge graph model for link prediction of novel phosphorylated substrates of kinases

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