Protein arginine methyltransferase 1 modulates innate immune responses through regulation of peroxisome proliferator-activated receptor γ-dependent macrophage differentiation

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 knockout 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 (PPAR gamma)-dependent M2 macrophage differentiation. PPAR gamma 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 PPAR gamma expression in response to IL4 treatment resulting in 4-fold lower PPAR gamma expression in knock-out cells than in wild-type cells. Detailed study of the mechanism revealed that PRMT1 regulates PPAR gamma gene expression through histone H4R3me2a methylation at the PPAR gamma promoter. Supplementing with PPAR gamma 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 PPAR gamma expression contributes to the infection susceptibility in PRMT1 knock-out mice.