IL-24 deficiency protects mice against bleomycin-induced pulmonary fibrosis by repressing IL-4-induced M2 program in macrophages

Rao, Lizong; Wang, Yi; Zhang, Lei; Wu, Guorao; Zhang, Lu; Wang, Fa-Xi; Chen, Longmin; Sun, Fei; Song, Jia; Zhang, Shu; Yu, Qilin; Wei, Jianghong; Lei, Huiren; Yuan, Ting; Li, Jinxiu; Huang, Xingxu; Cheng, Bin; Zhao, Jianping; Xu, Yu; Mo, Biwen; Wang, Cong Yi; Zhang, Huilan

doi:10.1038/s41418-020-00650-6

Cited by 66 publications

(42 citation statements)

References 47 publications

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“…Since our previous work 15 demonstrated that liposomes maybe uptake by macrophages and regulate macrophages polarization, we also assessed the impact of Srpx2 siRNA-loaded liposomes on macrophages. No obvious difference was detected on the polarization of alternative activated macrophages, which were one of major sources of TGF-β 1 ( Supplementary Figure 6 A). Additionally, the expression of Srpx2 also showed no difference following IL-4 stimulated macrophages ( Supplementary Figure 6 B), indicating that the protection of Srpx2 siRNA-loaded liposomes on pulmonary fibrosis is duo to suppression of fibroblasts behavior, not macrophages activation.…”

Section: Discussionmentioning

confidence: 97%

“…Idiopathic pulmonary fibrosis (IPF), a fatal lung interstitial disease, is characterized by progressive scarring of the pulmonary parenchyma with a median survival of only 2-3 years after diagnosis 1 . Although the new antifibrotic agents of Ofev (nintedanib) and Esbriet (pirfenidone) approved by FDA improve the wellbeing of patients, the prognosis of IPF remains poor with 5-year mortality rates still ranging from 70 to 80% 2 .…”

Section: Introductionmentioning

confidence: 99%

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Local administration of liposomal-based Srpx2 gene therapy reverses pulmonary fibrosis by blockading fibroblast-to-myofibroblast transition

Wang

Liu

et al. 2021

Theranostics

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Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fatal interstitial lung disease characterized by abnormal transition and proliferation of fibroblasts. The uncontrolled transition of fibroblasts, commonly known as myofibroblasts, are the principal source of the enormous extracellular matrix (ECM) depositing in lung parenchyma, leading to gradual failure of gas exchange and mortality of the patients. However, up to now, rare effective therapeutic strategies have been developed to blockade fibroblast-to-myofibroblast transition (FMT) in IPF. Method: We illustrated that the lungs originated from IPF patients and mice with pulmonary fibrosis are characterized by the overexpression of sushi-repeat-containing protein, X-linked 2 (SRPX2). Further functionality studies identified the pivotal role of SRPX2 in FMT. Mechanistically, SRPX2 was involved in a TGFβR1/SMAD3/SRPX2/AP1/SMAD7 positive feedback loop. Specifically, SRPX2 was upregulated by TGF-β1 in a TGFβR1/SMAD3-dependent manner, after which SRPX2 in turn repressed the expression of AP1, subsequently minimized SMAD7 expression, through which it reduced the formation of inhibitory complex with TGFβR1 and enhanced SMAD signaling pathway to promote FMT and exacerbate pulmonary fibrosis. Notably, intratracheal administration of siRNA-loaded liposomes could effectively suppress the expression of Srpx2 in the lung and remarkably protect mice against BLM-induced pulmonary fibrosis, concomitant with a significant reduction of FMT. Results: Accordingly, these data indicate that Srpx2 plays an essential role in the pathogenesis of pulmonary fibrosis and suggests the strategy aiming at silencing Srpx2 could be a promising therapeutic approach against pulmonary fibrosis in clinical settings.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Local administration of liposomal-based Srpx2 gene therapy reverses pulmonary fibrosis by blockading fibroblast-to-myofibroblast transition

Wang

Liu

et al. 2021

Theranostics

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“…Canonical XREs within enhancers exhibiting increased activity in response to WSP were identified in proximity to each of these genes. Autocrine/paracrine regulators of airway cell programming, such as CCN2 (CTGF), and the cytokine, IL24, which is implicated in lung and airway remodeling in response to different inflammatory stimuli, were also amongst the set of AHR targets we identified (66)(67)(68)(69). Thus, the short-lived primary transcriptional response to WSP mediated by AHR includes targets that likely contribute to more sustained changes in gene expression.…”

Section: Crosstalk Between Ahr and Nfkb Signaling In Response To Wspmentioning

confidence: 82%

Genomics-based deconvolution of multiplexed transcriptional responses to wood smoke particles defines rapid AHR signaling dynamics

Gupta

Sanford

et al. 2021

Preprint

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Transcriptional responses to wildfire smoke, an increasingly important cause of human morbidity, are poorly understood. Here, using a combination of precision nuclear run-on sequencing (PRO-seq) and the assay for transposase-accessible chromatin using sequencing (ATAC-seq), we identify rapid and dynamic changes in transcription and chromatin structure in Beas-2B airway epithelial cells after exposure to wood smoke particles (WSP). By comparing 30 and 120 minutes of WSP exposure, we defined three distinct temporal patterns of transcriptional induction and chromatin responses to WSP. Whereas transcription of canonical targets of the aryl hydrocarbon receptor (AHR), such as CYP1A1 and AHRR, was robustly increased after 30 minutes of WSP exposure, transcription of these genes and associated enhancers returned to near baseline at 120 minutes. ChIP-qPCR assays and AHR knockdown confirmed a role for AHR in regulating these transcriptional responses, and we applied bioinformatics approaches to identify novel AHR-regulated pathways and targets including the DNA methyltransferase, DNMT3L, and its interacting factor, SPOCD1. Our analysis also defined a role for NFkB as a primary transcriptional effector of WSP-induced changes in gene expression. The kinetics of AHR- and NFkB-regulated responses to WSP were distinguishable based on the timing of both transcriptional responses and chromatin remodeling, with induction of several cytokines implicated in maintaining the NFkB response. In aggregate, our data establish a direct and primary role for AHR in mediating airway epithelial responses to WSP and identify crosstalk between AHR and NFkB signaling in controlling pro-inflammatory gene expression.

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“…It is well known that the SOCS3-STAT6 pathway plays an important role in controlling macrophage polarization [ 23 , 28 , 29 ]. In order to investigate the effect of T. marneffei infection on the SOCS3-STAT6 pathway, we infected THP-1 macrophages (M0) with T. marneffei spores and measured the levels of SOCS3 mRNA and protein.…”

Section: Resultsmentioning

confidence: 99%

Talaromyces marneffei promotes M2-like polarization of human macrophages by downregulating SOCS3 expression and activating the TLR9 pathway

et al. 2021

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Little is known about how Talaromyces marneffei , a thermally dimorphic fungus that causes substantial morbidity and mortality in Southeast Asia, evades the human immune system. Polarization of macrophages into fungal-inhibiting M1-like and fungal-promoting M2-like types has been shown to play an important role in the innate immune response against fungal pathogens. This mechanism has not been defined for T. marneffei . Here, we demonstrated that T. marneffei promotes its survival in human macrophages by inducing them toward M2-like polarization. Our investigations of the mechanism revealed that T. marneffei infection led to SOCS3 protein degradation by inducing tyrosine phosphorylation, thereby relieving the inhibitory effect of SOCS3 on p-STAT6, a key factor for M2-like polarization. Our SOCS3-overexpression experiments showed that SOCS3 is a positive regulator of M1-like polarization and plays an important role in limiting M2-like polarization. Furthermore, we found that inhibition of the TLR9 pathway partially blocked T. marneffei -induced M2-like polarization and significantly enhanced the killing activity of macrophages against T. marneffei . Collectively, these results reveal a novel mechanism by which T. marneffei evades the immune response of human macrophages.

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IL-24 deficiency protects mice against bleomycin-induced pulmonary fibrosis by repressing IL-4-induced M2 program in macrophages

Cited by 66 publications

References 47 publications

Local administration of liposomal-based Srpx2 gene therapy reverses pulmonary fibrosis by blockading fibroblast-to-myofibroblast transition

Local administration of liposomal-based Srpx2 gene therapy reverses pulmonary fibrosis by blockading fibroblast-to-myofibroblast transition

Genomics-based deconvolution of multiplexed transcriptional responses to wood smoke particles defines rapid AHR signaling dynamics

Talaromyces marneffei promotes M2-like polarization of human macrophages by downregulating SOCS3 expression and activating the TLR9 pathway

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