Abstract
Although microRNA (miRNA) regulation of TLR signaling is well established, this has not yet been observed for NLR proteins or the inflammasomes they form. We have now validated a highly conserved miR-223 target site in the NLRP3 3'-untranslated region. miR-223 expression decreases as monocytes differentiate into macrophages, whereas NLRP3 protein increases during this time. However, overexpression of miR-223 prevents accumulation of NLRP3 protein and inhibits IL-1β production from the inflammasome. Virus inhibition of the inflammasome is an emerging theme, and we have also identified an EBV miRNA that can target the miR-223 binding site in the NLRP3 3'-untranslated region. Furthermore, this virus miRNA can be secreted from infected B cells via exosomes to inhibit the NLRP3 inflammasome in noninfected cells. Therefore, we have identified both the first endogenous miRNA that limits NLRP3 inflammatory capacity during myeloid cell development and also a viral miRNA that takes advantage of this, limiting inflammation for its own purposes.
Publication types
- Research Support, Non-U.S. Gov't
MeSH terms
- 3' Untranslated Regions / genetics
- Carrier Proteins / biosynthesis*
- Carrier Proteins / genetics
- Cell Differentiation / genetics
- Cell Differentiation / immunology
- Cell Line, Tumor
- Cell Lineage / genetics
- Cell Lineage / immunology
- Cells, Cultured
- HEK293 Cells
- Herpesvirus 4, Human / genetics
- Herpesvirus 4, Human / immunology*
- Humans
- Inflammasomes / antagonists & inhibitors
- Inflammasomes / biosynthesis*
- Inflammasomes / genetics
- Interleukin-1beta / antagonists & inhibitors
- Interleukin-1beta / biosynthesis*
- Interleukin-1beta / genetics
- Macrophages / cytology
- Macrophages / immunology
- Macrophages / virology
- MicroRNAs / genetics
- MicroRNAs / physiology*
- Monocytes / immunology
- Monocytes / metabolism
- Monocytes / virology
- Myeloid Cells / cytology
- Myeloid Cells / immunology
- Myeloid Cells / virology
- NLR Family, Pyrin Domain-Containing 3 Protein
- Protein Binding / genetics
- Protein Binding / immunology
- RNA, Viral / immunology
- Viral Matrix Proteins / genetics
- Viral Matrix Proteins / physiology*
Substances
- 3' Untranslated Regions
- Carrier Proteins
- EBV-associated membrane antigen, Epstein-Barr virus
- Inflammasomes
- Interleukin-1beta
- MIRN223 microRNA, human
- MicroRNAs
- NLR Family, Pyrin Domain-Containing 3 Protein
- NLRP3 protein, human
- RNA, Viral
- Viral Matrix Proteins