Abstract 649: PARP14 and PARP9 Are Novel Regulators of Macrophage Activation
Purpose: A microenvironment dominant in pro-inflammatory macrophages (“M1”) and lacking anti-inflammatory macrophages (“M2”) may promote vascular diseases. We explored and validated key regulators of such macrophage polarization.
Methods and Results: Using global proteomic analysis and bioinformatics, we examined the changes in the proteomes of mouse and human macrophage cell lines (RAW264.7; THP-1) in response to interferon gamma (IFNγ) or interleukin 4 (IL-4) for M1 or M2 polarization, respectively. Among 5816 proteins in RAW264.7 and 4723 in THP-1, data filtering and clustering identified poly(ADP-ribose) polymerase 14 (PARP14) and 9 (PARP9) as candidates for key regulators of macrophage polarization, which increase in M1 and decrease in M2 condition. siRNA silencing of PARP14 in macrophages induced M1 genes TNF-α, IL-1β and iNOS, while decreased M2 markers Arg1 and MRC1, indicating that PARP14 suppresses pro-inflammatory macrophage activation and promotes anti-inflammatory polarization. PARP14 silencing induced STAT1 phosphorylation and reduced STAT6 phosphorylation, suggesting their roles in the underlying signaling mechanisms. In contrast, PARP9 silencing decreased M1 markers, as well as phosphorylation of STAT1. Of interest, a direct physical interaction between PARP14 and PARP9 was also demonstrated. In vivo evidence supported these in vitro findings. Macrophages of PARP14-deficient mice expressed markedly higher levels of M1 genes and lower levels M2 markers. PARP14 deficiency accelerated lesion development after mechanical injury in femoral arteries.
Conclusions: PARP14 and PARP9 regulate macrophage activation, offering novel therapeutic targets for vascular diseases.
Author Disclosures: H. Iwata: None. P. Ricchiuto: None. T. Hara: Employment; Significant; Kowa Company, LTD. A. Sharma: None. A. Mojcher: None. D. Fukuda: None. A. Barabási: None. E. Aikawa: None. S. Singh: None. M. Aikawa: Research Grant; Significant; Kowa Company LTD..
- © 2014 by American Heart Association, Inc.