Ongoing research provides further understanding of the biology of RNase A ribonucleases that promote innate immunity (the eosinophil RNase 2 and RNase 3, tissue RNases 7 and 8, and leukocyte RNase A-2) with efforts focused toward understanding their mechanisms of action in health and disease. Eosinophil derived neurotoxin (EDN) and eosinophil cationic protein (ECP) are prominent, evolutionarily divergent secretory mediators of human eosinophils with antiviral activity. The mouse orthologs of these proteins, the eosinophil-associated ribonucleases, or EARs, have undergone an unusual pattern of evolution called rapid birth-death and gene sorting, which has also been documented in the T-cell receptor, immunoglobulin, and major-histocompatability complex gene families. This rapidly expanded gene family consists of 15 genes of which mEar-1, -2, -6/7, -5/11 have been positively identified within eosinophil secondary granules. Mouse EAR11 has retained the RNase A family characteristic sequence motifs but has a unique expression pattern, as it responds to Th2 stimulation, and is produced by alternatively-activated macrophages in the lung in response to IL-4 or IL-13. As part of a larger effort to evaluate the unique properties of mEAR11, we have compared the enzymatic activity of this protein to the predominant paralogs, mEAR1 and mEAR2. Despite similar isoelectric points (pI), mEAR11 has approximately 100-fold less activity against a standard tRNA substrate. Among the interpretations, it is conceivable that mEAR 11 has diverged to support functions other than enzymatic activity. Other evaluations of the bioactivity of mEAR 11 are currently in progress. We also report a mouse model that includes the first successful deletion of a mouse eosinophil ribonuclease (relevant also for report AI000941). The characterization of this mouse will have profound impact on our understanding of the role of these enzymes in promoting homeostasis in vivo and at the cellular level.

Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2013
Total Cost
$136,301
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Rosenberg, Helene F; Druey, Kirk M (2018) Modeling asthma: Pitfalls, promises, and the road ahead. J Leukoc Biol 104:41-48
Ma, M; Redes, J L; Percopo, C M et al. (2018) Alternaria alternata challenge at the nasal mucosa results in eosinophilic inflammation and increased susceptibility to influenza virus infection. Clin Exp Allergy 48:691-702
Foster, Paul S; Maltby, Steven; Rosenberg, Helene F et al. (2017) Modeling TH 2 responses and airway inflammation to understand fundamental mechanisms regulating the pathogenesis of asthma. Immunol Rev 278:20-40
Percopo, Caroline M; Brenner, Todd A; Ma, Michelle et al. (2017) SiglecF+Gr1hi eosinophils are a distinct subpopulation within the lungs of allergen-challenged mice. J Leukoc Biol 101:321-328
Kraemer, Laura S; Brenner, Todd A; Krumholz, Julia O et al. (2017) A flow-cytometric method to evaluate eosinophil-mediated uptake of probiotic Lactobacillus reuteri. J Microbiol Methods 137:19-24
Rosenberg, Helene F; Druey, Kirk M (2016) Eosinophils, galectins, and a reason to breathe. Proc Natl Acad Sci U S A 113:9139-41
Rosenberg, Helene F (2015) Eosinophil-Derived Neurotoxin (EDN/RNase 2) and the Mouse Eosinophil-Associated RNases (mEars): Expanding Roles in Promoting Host Defense. Int J Mol Sci 16:15442-55
Yamada, Kelsey J; Barker, Tolga; Dyer, Kimberly D et al. (2015) Eosinophil-associated ribonuclease 11 is a macrophage chemoattractant. J Biol Chem 290:8863-75
Percopo, Caroline M; Dyer, Kimberly D; Ochkur, Sergei I et al. (2014) Activated mouse eosinophils protect against lethal respiratory virus infection. Blood 123:743-52
Yang, Ming; Eyers, Fiona; Xiang, Yang et al. (2014) Expression profiling of differentiating eosinophils in bone marrow cultures predicts functional links between microRNAs and their target mRNAs. PLoS One 9:e97537

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