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

Pierdomenico, Anna M.; Patruno, Sara; Codagnone, Marilina; Simiele, Felice; Mari, Veronica Cecilia; Plebani, Roberto; Recchiuti, Antonio; Romano, Mario

doi:10.1038/s41598-017-14055-y

Cited by 22 publications

(23 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In an analysis of BAL fluid from people with CF, Cif was increased overall and correlated with decreased LXA 4 , increased IL‐8, and decreased lung function . In addition to decreased concentrations of LXA 4 in the CF airway, LXA4 signaling appears to be reduced in CF due to the overexpression of miR‐181, which decreases the expression of ALX/FPR2, the receptor that is recognized by LXA 4 . miR‐181 is increased and ALX/FPR2 is decreased in CF bronchial epithelial cell lines and monocyte‐derived macrophages (MDMs) from people with CF.…”

Section: Characteristics Of the Cystic Fibrosis Inflammatory Responsementioning

confidence: 99%

Inflammation in cystic fibrosis: An update

Roesch

Nichols

Chmiel

2018

Pediatric Pulmonology

188

191

View full text Add to dashboard Cite

Inflammation plays a critical role in cystic fibrosis (CF) lung pathology and disease progression making it an active area of research and important therapeutic target. In this review, we explore the most recent research on the major contributors to the exuberant inflammatory response seen in CF as well as potential therapeutics to combat this response. Absence of functional cystic fibrosis transmembrane conductance regulator (CFTR) alters anion transport across CF airway epithelial cells and ultimately results in dehydration of the airway surface liquid. The dehydrated airway surface liquid in combination with abnormal mucin secretion contributes to airway obstruction and subsequent infection that may serve as a trigger point for inflammation. There is also evidence to suggest that airway inflammation may be excessive and sustained relative to the infectious stimuli. Studies have shown dysregulation of both pro-inflammatory mediators such as IL-17 and pro-resolution mediators including metabolites of the eicosanoid pathway. Recently, CFTR potentiators and correctors have garnered much attention in the CF community. Although these modulators address the underlying defect in CF, their impact on downstream consequences such as inflammation are not known. Here, we review pre-clinical and clinical data on the impact of CFTR modulators on inflammation. In addition, we examine other cell types including neutrophils, macrophages, and T-lymphocytes that express CFTR and contribute to the CF inflammatory response. Finally, we address challenges in developing anti-inflammatory therapies and highlight some of the most promising anti-inflammatory drugs under development for CF.

show abstract

Section: Characteristics Of the Cystic Fibrosis Inflammatory Responsementioning

confidence: 99%

Inflammation in cystic fibrosis: An update

Roesch

Nichols

Chmiel

2018

Pediatric Pulmonology

188

191

View full text Add to dashboard Cite

show abstract

“…As well as dysfunctional autophagy, CF macrophages also display impaired phagocytosis. CF macrophages have increased miR-181b and thus lower levels of its target, a cell surface receptor recognised by lipoxin A4 [135]. Inhibiting miR-181b restores lipoxin A4-induced phagocytic ability [135].…”

Section: Mirnas In Cfmentioning

confidence: 99%

Alpha-1 Antitrypsin—A Target for MicroRNA-Based Therapeutic Development for Cystic Fibrosis

Hunt

Glasgow

Humphreys

et al. 2020

IJMS

View full text Add to dashboard Cite

Cystic fibrosis (CF) is an autosomal recessive genetic disorder arising from mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Disruption to normal ion homeostasis in the airway results in impaired mucociliary clearance, leaving the lung more vulnerable to recurrent and chronic bacterial infections. The CF lung endures an excess of neutrophilic inflammation, and whilst neutrophil serine proteases are a crucial part of the innate host defence to infection, a surplus of neutrophil elastase (NE) is understood to create a net destructive effect. Alpha-1 antitrypsin (A1AT) is a key antiprotease in the control of NE protease activity but is ineffective in the CF lung due to the huge imbalance of NE levels. Therapeutic strategies to boost levels of protective antiproteases such as A1AT in the lung remain an attractive research strategy to limit the damage from excess protease activity. microRNAs are small non-coding RNA molecules that bind specific cognate sequences to inhibit expression of target mRNAs. The inhibition of miRNAs which target the SERPINA1 (A1AT-encoding gene) mRNA represents a novel therapeutic approach for CF inflammation. This could involve the delivery of antagomirs that bind and sequester the target miRNA, or target site blockers that bind miRNA recognition elements within the target mRNA to prevent miRNA interaction. Therefore, miRNA targeted therapies offer an alternative strategy to drive endogenous A1AT production and thus supplement the antiprotease shield of the CF lung.

show abstract

“…MicroRNAs have emerged as important regulators in human physiological and pathological cell processes including the immune system, providing negative feedback regulation of inflammation and ion transport. In CF, microRNA profiling studies have shown that miR155, miR145, miR223, miR494, miR99b, let-7e, miR181b, and miR125a are increased in CF airway epithelial cell lines, CF bronchial brushing samples, and macrophages, compared to non-CF controls ( McKiernan and Greene, 2015 ; Pierdomenico et al, 2017 ). In contrast, miR126, miR31, miR17 expression is decreased in CF airway epithelial cells.…”

Section: Inflammation In Cf Airwaymentioning

confidence: 99%

“…Many actions exerted by SPMs to limit infection have been described in non-CF cells isolated from human and mice macrophages, ( Chiang et al, 2012 ; Colas et al, 2016 ; Pierdomenico et al, 2017 ; Codagnone et al, 2018 ) ( Table 3 ). In addition, SPMs (PDn-3DPA, RvD1, and RvD2) stimulate macrophage differentiation from a pro-inflammatory (M1) to a pro-resolutive phenotype (M2) in non-CF models ( Dalli and Serhan, 2012 ; Recchiuti et al, 2014 ; Croasdell et al, 2015 ; Pistorius et al, 2018 ) and enhance the expression of surface receptors involved in the uptake of apoptotic cells ( Matte et al, 2019 ) ( Table 3 ).…”

Section: Impact Of Spm S Demonstrated In Cf Modelsmentioning

confidence: 99%

“…LXA4 also attenuates renal fibrosis by inducing let-7c ( Brennan et al, 2013 ). Furthermore, miR-181b which is overexpressed in CF macrophages and airway epithelial cells, down-regulates the expression of the FPR2 receptor and the pro-resolution signaling pathways ( Pierdomenico et al, 2015 ; Pierdomenico et al, 2017 ) ( Table 5 ).…”

Section: Other Possible Impacts Of Spm S On Alterementioning

confidence: 99%

See 1 more Smart Citation

The Role of Specialized Pro-Resolving Mediators in Cystic Fibrosis Airways Disease

2020

View full text Add to dashboard Cite

Cystic Fibrosis (CF) is a recessive genetic disease due to mutations of the Cystic Fibrosis Transmembrane Conductance Regulator ( CFTR ) gene encoding the CFTR chloride channel. The ion transport abnormalities related to CFTR mutation generate a dehydrated airway surface liquid (ASL) layer, which is responsible for an altered mucociliary clearance, favors infections and persistent inflammation that lead to progressive lung destruction and respiratory failure. The inflammatory response is normally followed by an active resolution phase to return to tissue homeostasis, which involves specialized pro-resolving mediators (SPMs). SPMs promote resolution of inflammation, clearance of microbes, tissue regeneration and reduce pain, but do not evoke unwanted immunosuppression. The airways of CF patients showed a decreased production of SPMs even in the absence of pathogens. SPMs levels in the airway correlated with CF patients’ lung function. The prognosis for CF has greatly improved but there remains a critical need for more effective treatments that prevent excessive inflammation, lung damage, and declining pulmonary function for all CF patients. This review aims to highlight the recent understanding of CF airway inflammation and the possible impact of SPMs on functions that are altered in CF airways.

show abstract

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

Cited by 22 publications

References 52 publications

Inflammation in cystic fibrosis: An update

Inflammation in cystic fibrosis: An update

Alpha-1 Antitrypsin—A Target for MicroRNA-Based Therapeutic Development for Cystic Fibrosis

The Role of Specialized Pro-Resolving Mediators in Cystic Fibrosis Airways Disease

Contact Info

Product

Resources

About