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 responsesin 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 γ (PPARγ)-dependent M2 macrophage differentiation. PPARγ 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 PPARγ expression in response to IL4 treatment resulting in 4-fold lower PPARγ expression in knock-out cells than in wild-type cells. Detailed study of the mechanism revealed that PRMT1 regulates PPARγ gene expression through histone H4R3me2a methylation at the PPARγ promoter. Supplementing with PPARγ agonists rosiglitazone and GW1929 was sufficient to restore M2 differentiationin vivoandin vitroand abrogated the difference in survival between wild-type and PRMT1 knock-out mice. Taken together these data suggest that PRMT1-dependent regulation of macrophage PPARγ expression contributes to the infection susceptibility in PRMT1 knock-out mice.
From the Department of Internal Medicine and.
Irina
I
Tikhanovich
From the Department of Internal Medicine and.
Jie
J
Zhao
From the Department of Internal Medicine and.
Jody
J
Olson
From the Department of Internal Medicine and.
Abby
A
Adams
From the Department of Internal Medicine and.
Ryan
R
Taylor
the Liver Center, University of Kansas Medical Center, Kansas City, Kansas 66160.
Brian
B
Bridges
the Liver Center, University of Kansas Medical Center, Kansas City, Kansas 66160.
Laurie
L
Marshall
the Liver Center, University of Kansas Medical Center, Kansas City, Kansas 66160.
Benjamin
B
Roberts
From the Department of Internal Medicine and sweinman@kumc.edu.|the Liver Center, University of Kansas Medical Center, Kansas City, Kansas 66160.
Steven A
SA
Weinman
D000818:Animals; D000906:Antibodies / Q000737:chemistry; D001120:Arginine / Q000737:chemistry; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D015847:Interleukin-4 / Q000494:pharmacology; D008070:Lipopolysaccharides; D008103:Liver Cirrhosis / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000166:cytology; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology; D047495:PPAR gamma / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D018805:Sepsis / Q000378:metabolism
D000906:Antibodies; D016207:Cytokines; D006657:Histones; D008070:Lipopolysaccharides; D047495:PPAR gamma; D012097:Repressor Proteins; D015847:Interleukin-4; D001120:Arginine; C099988:PRMT1 protein, human; C546338:Prmt1 protein, mouse; D011484:Protein-Arginine N-Methyltransferases
arginine methylation; cecal ligation and puncture; differentiation; histone arginine methylation; innate immunity; macrophage; monocyte; sepsis