Long Noncoding RNA GAS5 Regulates Macrophage Polarization and Diabetic Wound Healing

Hu, Junyi; Zhang, Liping; Liechty, Cole; Zgheib, Carlos; Hodges, Maggie M.; Liechty, Kenneth W.; Xu, Jie

doi:10.1016/j.jid.2019.12.030

Cited by 72 publications

(61 citation statements)

References 37 publications

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“…Since macrophages exist in an array of activation states, it is possible that in vivo CD68 + F4/80 + -macrophages may represent specific and special subpopulations of macrophages. Moreover, despite the known low stiffness of fat tissue, the resident macrophages present in chronic, non-resolving diabetic wounds or inflamed adipose tissue express mainly “M1” markers ( 66 , 67 ). However, macrophages present in normal healthy adipose tissue express mainly “M2” markers ( 67 ).…”

Section: Discussionmentioning

confidence: 99%

TRPV4 Plays a Role in Matrix Stiffness-Induced Macrophage Polarization

2020

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Phenotypic polarization of macrophages is deemed essential in innate immunity and various pathophysiological conditions. We have now determined key aspects of the molecular mechanism by which mechanical cues regulate macrophage polarization. We show that Transient Receptor Potential Vanilloid 4 (TRPV4), a mechanosensitive ion channel, mediates substrate stiffness-induced macrophage polarization. Using atomic force microscopy, we showed that genetic ablation of TRPV4 function abrogated fibrosis-induced matrix stiffness generation in skin tissues. We have determined that stiffer skin tissue promotes the M1 macrophage subtype in a TRPV4-dependent manner; soft tissue does not. These findings were further validated by our in vitro results which showed that stiff matrix (50 kPa) alone increased expression of macrophage M1 markers in a TRPV4-dependent manner, and this response was further augmented by the addition of soluble factors; neither of which occurred with soft matrix (1 kPa). A direct requirement for TRPV4 in M1 macrophage polarization spectrum in response to increased stiffness was evident from results of gain-of-function assays, where reintroduction of TRPV4 significantly upregulated the expression of M1 markers in TRPV4 KO macrophages. Together, these data provide new insights regarding the role of TRPV4 in matrix stiffness-induced macrophage polarization spectrum that may be explored in tissue engineering and regenerative medicine and targeted therapeutics.

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Section: Discussionmentioning

confidence: 99%

TRPV4 Plays a Role in Matrix Stiffness-Induced Macrophage Polarization

2020

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“…However, unlike our findings of the pro-M1 phenotype by GAS5, other studies have shown a pro-M2 phenotype. Hu et al showed that overexpression of GAS5 promoted macrophage (RAW) polarization toward an M1 phenotype by inducing nitric oxide synthase (iNOS), IL-1b, and TNF-a compared with the empty vector control (49). GAS5-mediated increase in the proinflammatory cytokines IL-6, IL-1b, and TNF-a was shown in ox-LDL-induced THP-1 macrophages (50).…”

Section: Discussionmentioning

confidence: 99%

“…GAS5 was identified in a screening of genes expressed in G0 serum-starved NIH/3T3 cells ( 48 ). Overexpression of GAS5 appeared as a strategy for the tumor therapeutics via inducing apoptosis and concomitant attenuated cell proliferation ( 49 ). Similar to the lncRNA RN7SK function, GAS5 also significantly increases MHCII (M1 marker) and inhibits CD163 and CD206 (albeit not significant) expression at the same time.…”

Section: Discussionmentioning

confidence: 99%

Long Non-coding RNAs RN7SK and GAS5 Regulate Macrophage Polarization and Innate Immune Responses

et al. 2020

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Macrophages (Mφ) are immune cells that exhibit remarkable functional plasticity. Identification of novel endogenous factors that can regulate plasticity and innate immune functions of Mφ will unravel new strategies to curb immune-related diseases. Long non-coding RNAs (lncRNAs) are a class of endogenous, non-protein coding, regulatory RNAs that are increasingly being associated with various cellular functions and diseases. Despite their ubiquity and abundance, lncRNA-mediated epigenetic regulation of Mφ polarization and innate immune functions is poorly studied. This study elucidates the regulatory role of lncRNAs in monocyte to Mφ differentiation, M1/M2 dichotomy and innate immune responses. Expression profiling of eighty-eight lncRNAs in monocytes and in vitro differentiated M2 Mφ identified seventeen differentially expressed lncRNAs. Based on fold-change and significance, we selected four differentially expressed lncRNAs viz., RN7SK, GAS5, IPW, and ZFAS1 to evaluate their functional impact. LncRNA knockdown was performed on day 3 M2 Mφ and the impact on polarization was assessed on day 7 by surface marker analysis. Knockdown of RN7SK and GAS5 showed downregulation of M2 surface markers (CD163, CD206, or Dectin) and concomitant increase in M1 markers (MHC II or CD23). RN7SK or GAS5 knockdown showed no significant impact on CD163, CD206, or CD23 transcripts. M1/M2 markers were not impacted by IPW or ZFAS1 knockdown. Functional regulation of antigen uptake/processing and phagocytosis, two central innate immune pathways, by candidate lncRNA was assessed in M1/M2 Mφ. Compared to scramble, enhanced antigen uptake and processing were observed in both M1/M2 Mφ transfected with siRNA targeting GAS5 and RN7SK but not IPW and ZFAS1. In addition, knockdown of RN7SK significantly augmented uptake of labelled E. coli in vitro by M1/M2 Mφ, while no significant difference was in GAS5 silencing cells. Together, our results highlight the instrumental role of lncRNA (RN7SK and GAS5)-mediated epigenetic regulation of macrophage differentiation, polarization, and innate immune functions.

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“…However, it is an important factor in explaining a possible mechanism of CAD. Among the 26 lncRNAs, GAS5, CRNDE, HCG22, and XIST were associated with inflammation [ 48 – 51 ], while the rest have not been reported previously. GAS5 and XIST have been extensively researched in previous reports.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of ceRNA Regulation Network Involved in the Development of Coronary Artery Disease

Zhang

et al. 2021

BioMed Research International

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Background. Coronary artery disease (CAD) is one of the most common causes of sudden death with high morbidity in recent years. This paper is aimed at exploring the early peripheral blood biomarkers of sudden death and providing a new perspective for clinical diagnosis and forensic pathology identification by integrated bioinformatics analysis. Methods. Two microarray expression profiling datasets (GSE113079 and GSE31568) were downloaded from the Gene Expression Omnibus (GEO) database, and we identified differentially expressed lncRNAs, miRNAs, and mRNAs in CAD. Gene Ontology (GO) and KEGG pathway analyses of DEmRNAs were executed. A protein-protein interaction (PPI) network was constructed, and hub genes were identified. Finally, we constructed a competitive endogenous RNA (ceRNA) regulation network among lncRNAs, miRNAs, and mRNAs. Also, the 5 miRNAs of the ceRNA network were verified by RT-PCR. Results. In total, 86 DElncRNAs, 148 DEmiRNAs, and 294 DEmRNAs were dysregulated in CAD. We received 12 GO terms and 5 pathways of DEmRNAs. 31 nodes and 78 edges were revealed in the PPI network. The top 10 genes calculated by degree method were identified as hub genes. Moreover, there were a total of 26 DElncRNAs, 5 DEmiRNAs, and 13 DEmRNAs in the ceRNA regulation network. We validated the 5 miRNAs of the ceRNA network by RT-PCR, which were consistent with the results of the microarray. Conclusions. In this paper, a CAD-specific ceRNA network was successfully constructed, contributing to the understanding of the relationship among lncRNAs, miRNAs, and mRNAs. We identified potential peripheral blood biomarkers in CAD and provided novel insights into the development and progress of CAD.

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Long Noncoding RNA GAS5 Regulates Macrophage Polarization and Diabetic Wound Healing

Cited by 72 publications

References 37 publications

TRPV4 Plays a Role in Matrix Stiffness-Induced Macrophage Polarization

TRPV4 Plays a Role in Matrix Stiffness-Induced Macrophage Polarization

Long Non-coding RNAs RN7SK and GAS5 Regulate Macrophage Polarization and Innate Immune Responses

Comprehensive Analysis of ceRNA Regulation Network Involved in the Development of Coronary Artery Disease

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