The role of microRNA-223 in acute lung injury (ALI
Final Report Abstract
MiRNAs constitute a family of short noncoding RNA molecules of 20 to 25 nucleotides in length that regulate gene expression at the posttranscriptional level. They are involved in the control of a wide range of biological functions and processes and bio-informatic predictions indicate that mammalian miRNAs can regulate approximately 30% of all protein-coding genes. In addition to this critical role in intracellular gene regulation – most recently, miRNAs were found to be also involved in cell-to-cell crosstalk. Thereby intercellular microRNA shuttling can mediate communication between critical effector cells during pathological states such as inflammation. In particular little is known about inflammatory-gene repression by miRNAs during inflammatory lung disease such as acute lung injury (ALI). Since inflammatory cells, in the acute early phase predominately neutrophils (PMNs), come into close spatial relationship with lung resident cells (including alveolar epithelial cells) we hypothesized that transfer of PMN-derived microRNAs into alveolar epithelia functions to repress inflammatory gene expression during acute lung injury (ALI). Alveolar-epithelial microRNA profiling following PMN-epithelial co-culture revealed a selective increase (over 100-fold) of miR-223 within alveolar epithelia. Analysis of PMN-derived supernatants showed activation-dependent release of miR-223 and subsequent transfer into alveolar epithelia during co-culture in vitro or following ventilator-induced ALI in vivo. Genetic studies indicate that miR-223-deficiency is associated with severe lung inflammation, while pulmonary overexpression of miR-223 provides protection during ALI. Studies of putative pulmonary-epithelial miR-223 target genes implicate repression of PARP-1 in miR-223-dependent attenuation of lung inflammation. Together, these findings identify intercellular transfer of genetic information via miR-223 shuttling from neutrophils into alveolar epithelia in an endogenous feedback-loop to dampen lung inflammation via repression of its inflammatory target gene PARP-1.
Publications
- Neutrophil Intercellular Communication in Acute Lung Injury: Emerging Roles of Microparticles and Gap Junctions. Am J Respir Cell Mol Biol 49 (2013) 1-5
Viola Dengler, Gregory P. Downey, Rubin M. Tuder, Holger K. Eltzschig, Eric P. Schmidt
- Neutrophil transfer of miR-223 to lung epithelial cells dampens acute lung injury in mice. Science Translational Medicine 20 Sep 2017:
Vol. 9, Issue 408, eaah5360
Viola Neudecker, Kelley S. Brodsky, Eric T. Clambey, Eric P. Schmidt, Thomas A. Packard, Bennett Davenport, Theodore J. Standiford, Tingting Weng, Ashley A. Fletcher, Lea Barthel, Joanne C. Masterson, Glenn T. Furuta, Chunyan Cai, Michael R. Blackburn, Ad
(See online at https://doi.org/10.1126/scitranslmed.aah5360)
