Emerging role of cystic fibrosis transmembrane conductance regulator as an epigenetic regulator: linking environmental cues to microRNAs

Chan, Hsiao Chang; Jiang, Xiaohua; Ruan, Ye Chun

doi:10.1111/1440-1681.12271

Cited by 7 publications

(7 citation statements)

References 146 publications

(131 reference statements)

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“…3 ). Together, these data support the emerging concept of CFTR as epigenetic modulator 39 . Along these lines, it has been recently reported that CFTR regulates miR-125b expression with a bicarbonate-dependent mechanism 40 .…”

Section: Discussionsupporting

confidence: 74%

microRNA-181b is increased in cystic fibrosis cells and impairs lipoxin A4 receptor-dependent mechanisms of inflammation resolution and antimicrobial defense

Pierdomenico

Patruno

Codagnone

et al. 2017

Sci Rep

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The involvement of microRNA (miR) in cystic fibrosis (CF) pathobiology is rapidly emerging. We previously documented that miR-181b controls the expression of the ALX/FPR2 receptor, which is recognized by the endogenous proresolution ligand, lipoxin (LX)A4. Here, we examined whether the miR-181b-ALX/FPR2 circuit was altered in CF. We examined human airways epithelial cells, normal (16HBE14o-), carrying the ΔF508 mutation (CFBE41o-) or corrected for this mutation (CFBE41o-/CEP-CFTR wt 6.2 kb), as well as monocyte-derived macrophages (MΦs) from CF patients. CFBE41o- cells exhibited higher miR-181b and reduced ALX/FPR2 levels compared to 16HBE14o- and CFBE41o-/CEP-CFTR wt 6.2 kb cells. An anti-mir-181b significantly enhanced ALX/FPR2 expression (+ 60%) as well as LXA4-induced increase in transepithelial electric resistance (+ 25%) in CFBE41o- cells. MΦs from CF patients also displayed increased miR-181b (+ 100%) and lower ALX/FPR2 levels (− 20%) compared to healthy cells. An anti-mir-181b enhanced ALX/FPR2 expression (+ 40%) and normalized receptor-dependent LXA4-induced phagocytosis of fluorescent-labeled zymosan particles as well as of Pseudomonas aeruginosa by CF-MΦs. These results provide the first evidence that miR-181b is overexpressed in CF cells, impairing some mechanisms of the ALX/FPR2-dependent pathway of inflammation resolution. Thus, targeting miR-181b may represent a strategy to enhance anti-inflammatory and anti-microbial defense mechanisms in CF.

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Section: Discussionsupporting

confidence: 74%

microRNA-181b is increased in cystic fibrosis cells and impairs lipoxin A4 receptor-dependent mechanisms of inflammation resolution and antimicrobial defense

Pierdomenico

Patruno

Codagnone

et al. 2017

Sci Rep

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“…The complex relationship between autoinflammation, CFTR, innate immunity and infection is poorly understood, and may be related to macrophage dysfunction, abnormal phagocytic killing of P. aeruginosa , and impaired degranulation of antimicrobial proteins through defective activation of the GTP‐binding protein Rab27a . In addition, CFTR dysfunction results in increased sensitivity to LPS (a major constituent of the outer membrane of Gram‐negative bacteria) stimulation, altered inflammatory signalling caused by abnormal neutrophil extracellular trap formation , and activation of microRNAs (miRNAs) and NF‐κB. These bacteria trigger the NLRP3 inflammasome through cytosolic receptors, resulting in increased caspase‐1 protease and IL‐1β and IL‐18 production (Fig.…”

Section: Autoinflammation and Infectionmentioning

confidence: 99%

The burgeoning field of innate immune‐mediated disease and autoinflammation

Peckham

Scambler

Savic

et al. 2016

The Journal of Pathology

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Immune-mediated autoinflammatory diseases are occupying an increasingly prominent position among the pantheon of debilitating conditions that afflict humankind. This review focuses on some of the key developments that have occurred since the original description of autoinflammatory disease in 1999, and focuses on underlying mechanisms that trigger autoinflammation. The monogenic autoinflammatory disease range has expanded considerably during that time, and now includes a broad spectrum of disorders, including relatively common conditions such as cystic fibrosis and subsets of systemic lupus erythematosus. The innate immune system also plays a key role in the pathogenesis of complex inflammatory disorders. We have proposed a new nomenclature to accommodate the rapidly increasing number of monogenic disorders, which predispose to either autoinflammation or autoimmunity or, indeed, combinations of both. This new terminology also encompasses a wide spectrum of genetically determined autoinflammatory diseases, with variable clinical manifestations of immunodeficiency and immune dysregulation/autoimmunity. We also explore some of the ramifications of the breakthrough discovery of the physiological role of pyrin and the search for identifiable factors that may serve to trigger attacks of autoinflammation. The evidence that pyrin, as part of the pyrin inflammasome, acts as a sensor of different inactivating bacterial modification Rho GTPases, rather than interacting directly with these microbial products, sets the stage for a better understanding of the role of microorganisms and infections in the autoinflammatory disorders. Finally, we discuss some of the triggers of autoinflammation as well as potential therapeutic interventions aimed at enhancing autophagy and proteasome degradation pathways.

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“…More interestingly, the CFTR/HCO 3 − /sAC/cAMP pathway was found to regulate miR‐125 in the embryo, through PKA and NFkB activation, which suppresses the p53‐mediated development arrest . This provides the first evidence for the involvement of the CFTR/HCO 3 − /sAC/cAMP signalling in epigenetic regulation . As in the case of sperm capacitation, Cl − is also required for preimplantation development.…”

Section: Cftr/hco3−‐dependent Sac Signallingmentioning

confidence: 80%

Amplification of FSH signalling by CFTR and nuclear soluble adenylyl cyclase in the ovary

Chen

Chan

2017

Clin Exp Pharma Physio

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Summary The cAMP/PKA pathway is one of the most important signalling pathways widely distributed in most eukaryotic cells. The activation of the canonical cAMP/PKA pathway depends on transmembrane adenylyl cyclase (tmAC). Recently, soluble adenylyl cyclase (sAC), which is activated by HCO3− or Ca2+, emerges to provide an alternative way to activate cAMP/PKA pathway with the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP‐activated Cl−/HCO3−‐conducting anion channel, as a key player. This review summarizes new progress in the investigation of the CFTR/HCO3−‐dependent sAC signalling and its essential role in various reproductive processes, particularly in ovarian functions. We present the evidence for a CFTR/HCO3−‐dependent nuclear sAC signalling cascade that amplifies the FSH‐stimulated cAMP/PKA pathway, traditionally thought to involve tmAC, in granulosa for the regulation of oestrogen production and granulosa cell proliferation. The implication of the CFTR/HCO3−/sAC pathway in amplifying other receptor‐activated cAMP/PKA signalling in a wide variety of cell types and pathophysiological processes, including aging, is also discussed.

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Emerging role of cystic fibrosis transmembrane conductance regulator as an epigenetic regulator: linking environmental cues to microRNAs

Cited by 7 publications

References 146 publications

microRNA-181b is increased in cystic fibrosis cells and impairs lipoxin A4 receptor-dependent mechanisms of inflammation resolution and antimicrobial defense

microRNA-181b is increased in cystic fibrosis cells and impairs lipoxin A4 receptor-dependent mechanisms of inflammation resolution and antimicrobial defense

The burgeoning field of innate immune‐mediated disease and autoinflammation

Amplification of FSH signalling by CFTR and nuclear soluble adenylyl cyclase in the ovary

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