| First Author | Tikhanovich I | Year | 2017 |
| Journal | J Biol Chem | Volume | 292 |
| Issue | 17 | Pages | 6882-6894 |
| PubMed ID | 28330868 | Mgi Jnum | J:242496 |
| Mgi Id | MGI:5905498 | Doi | 10.1074/jbc.M117.778761 |
| Citation | Tikhanovich I, et al. (2017) Protein arginine methyltransferase 1 modulates innate immune responses through regulation of peroxisome proliferator-activated receptor gamma-dependent macrophage differentiation. J Biol Chem 292(17):6882-6894 |
| abstractText | Arginine methylation is a common posttranslational modification that has been shown to regulate both gene expression and extranuclear signaling events. We recently reported defects in protein arginine methyltransferase 1 (PRMT1) activity and arginine methylation in the livers of cirrhosis patients with a history of recurrent infections. To examine the role of PRMT1 in innate immune responses in vivo, we created a cell type-specific knock-out mouse model. We showed that myeloid-specific PRMT1 knock-out mice demonstrate higher proinflammatory cytokine production and a lower survival rate after cecal ligation and puncture. We found that this defect is because of defective peroxisome proliferator-activated receptor gamma (PPARgamma)-dependent M2 macrophage differentiation. PPARgamma is one of the key transcription factors regulating macrophage polarization toward a more anti-inflammatory and pro-resolving phenotype. We found that PRMT1 knock-out macrophages failed to up-regulate PPARgamma expression in response to IL4 treatment resulting in 4-fold lower PPARgamma expression in knock-out cells than in wild-type cells. Detailed study of the mechanism revealed that PRMT1 regulates PPARgamma gene expression through histone H4R3me2a methylation at the PPARgamma promoter. Supplementing with PPARgamma agonists rosiglitazone and GW1929 was sufficient to restore M2 differentiation in vivo and in vitro and abrogated the difference in survival between wild-type and PRMT1 knock-out mice. Taken together these data suggest that PRMT1-dependent regulation of macrophage PPARgamma expression contributes to the infection susceptibility in PRMT1 knock-out mice. |
