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MicroRNA-223 suppresses inflammation by down regulating NF-kB activation in epithelial cells

ABSTRACT: MicroRNA-223, a principal myeloid-specific anti-inflammatory microRNA, is dysregulated in numerous inflammatory conditions and cancers. We found that miR-223 deficient zebrafish displayed augmented neutrophilic inflammation, which was due primarily to elevated activation of the canonical NF-B pathway. To our surprise, the NF-B over-activation was restricted to the basal epithelial cells, a squamous layer permeable to oxygen and chemicals. MiR-223 was expressed in epithelial cells and directly down-regulated multiple components in the NF-B signaling pathway in zebrafish and human. Both phagocytic and epithelial miR-223 suppressed neutrophil wound response and NF-B activation in the basal epithelial cells. Together, our data provide the mechanism of the multifaceted role of miR-223 and highlight the previously overlooked relevance of epithelial cells in miR-223 related diseases.

ORGANISM(S): Danio rerio

PROVIDER: GSE94996 | GEO | 2017/02/17

SECONDARY ACCESSION(S): PRJNA375098

REPOSITORIES: GEO

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Project description:Acute lung injury (ALI) is characterized by acute respiratory failure in the setting of non-cardiogenic pulmonary edema, causing acute respiratory distress syndrome (ARDS) in patients and contributes significantly to mortality of critically illness. The main goal of our study is to elucidate the role of miRNAs in neutrophil-epithelial communication during pulmonary inflammation and thereby identifying novel targets for therapy of acute lung injury (ALI). In our studies we identified a miR-223-dependent neutrophil-epithelial crosstalk during ALI. Activated neutrophils (PMN) and pulmonary epithelial cells come into a close spatial relationship during ALI. And, since previous studies had indicated the possibility that inflammatory cell-dependent release of miRNA-containing microvesicles could function as a means of exchanging genetic information from a donor to a target cell, we assessed PMN-elicited alterations of pulmonary epithelial miRNA expression in an experimental co-culture setup. This approach provided a selective and extremely robust readout: While other miRNAs were not or only moderately altered in their expression, pulmonary-epithelial-expressed miR-223 was significantly induced after 4 or 6h of co-incubation. Additional in vitro and in vivo studies clearly demonstrate that this increase of epithelial miR-223 is not due to miR-223 transcriptional induction, but instead PMN-dependent and caused by shuttling miR-223 from PMN into pulmonary epithelial cells. To address the functional role of miR-223-dependent neutrophil-epithelial crosstalk during ALI, we exposed mice to ventilator-induced ALI and observed robust induction of pulmonary miR-223 during ALI, while increases of miR-223 were completely abolished after antibody-depletion of PMN. Moreover, studies of alveolar epithelial cells isolated from mice with ALI showed robust increases of miR-223, indicating that miR-223 is shuttled from PMN towards alveolar epithelia during ALI in vivo. Functional studies revealed that gene-targeted mice for miR-223 experience a more severe phenotype during ALI as compared to controls, while their phenotype could be resuscitated by nanoparticle-mediated overexpression of miR-223 in the lungs. In summary, these studies reveal a novel role of miR-223-dependent neutrophil-epithelial crosstalk representing an anti-inflammatory pathway that can be targeted for ALI treatment.

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MicroRNA-223 suppresses inflammation by down regulating NF-kB activation in epithelial cells

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