PARP9 and PARP14 cross-regulate macrophage activation via STAT1 ADP-ribosylation

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Reprograming Model of Human Monocyte-derived Macrophages for In-vitro Assays
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Reprograming Model of Human Monocyte-derived Macrophages for In-vitro Assays

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Hiroshi Iwata1, Claudia Goettsch1, Amitabh Sharma2,3

  • 1Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

Nature Communications
|November 1, 2016
PubMed

Insights

Poly(ADP-ribose) polymerases 9 and 14 (PARP9 and PARP14) oppositely regulate macrophage activation, influencing vascular disease pathways. Their cross-regulation impacts inflammatory responses in arteries.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cardiovascular Research

Background:

  • Macrophage activation is critical in vascular disease, but its regulatory mechanisms are not fully understood.
  • Interferon-gamma (IFNγ) and Interleukin-4 (IL-4) induce distinct macrophage polarization states (M(IFNγ) and M(IL-4)).

Purpose of the Study:

  • To elucidate the roles of PARP9 and PARP14 in regulating macrophage activation.
  • To investigate the molecular mechanisms by which PARP9 and PARP14 control inflammatory signaling pathways.
  • To explore the association of PARP9 and PARP14 with human coronary artery disease and their in vivo relevance.

Main Methods:

  • Global proteomic analysis of macrophage cell lines stimulated with IFNγ or IL-4.
  • Silencing of PARP9 and PARP14 in primary macrophages.
  • Analysis of STAT1 and STAT6 phosphorylation.
  • Assessment of ADP-ribosylation of STAT1.
  • Network analysis to link PARP proteins with human coronary artery disease.
  • In vivo studies using PARP14-deficient mice.

Main Results:

  • PARP9 and PARP14 were identified as key regulators of macrophage activation.
  • PARP14 silencing promoted pro-inflammatory gene expression and STAT1 phosphorylation in M(IFNγ) cells, while suppressing anti-inflammatory genes and STAT6 phosphorylation in M(IL-4) cells.
  • PARP9 silencing inhibited pro-inflammatory genes and STAT1 phosphorylation in M(IFNγ) cells.
  • PARP14-mediated ADP-ribosylation of STAT1 was suppressed by PARP9; mutations at these sites increased STAT1 phosphorylation.
  • Network analysis revealed a link between PARP9-PARP14 and coronary artery disease.
  • PARP14 deficiency in hematopoietic cells exacerbated arterial lesion development and inflammation in mice.

Conclusions:

  • PARP9 and PARP14 exhibit opposing regulatory roles in macrophage activation.
  • PARP9 and PARP14 modulate inflammatory and anti-inflammatory signaling pathways through STAT protein modification.
  • These findings highlight PARP9 and PARP14 as potential therapeutic targets in vascular diseases like coronary artery disease.

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