Transcriptional reprogramming and resistance to colonic mucosal injury in poly (ADP-ribose) polymerase 1 (PARP1) deficient mice

Claire B. Larmonier, Kareem W. Shehab, Daniel Laubitz, Deepa R. Jamwal, Fayez K. Ghishan, Pawel R. Kiela

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Poly(ADP-ribose) polymerases (PARPs) synthesize and bind branched polymers of ADP-ribose to acceptor proteins using NAD as a substrate and participate in the control of gene transcription and DNA repair. PARP1, the most abundant isoform, regulates the expression of proinflammatory mediator cytokines, chemokines, and adhesion molecules, and inhibition of PARP1 enzymatic activity reduced or ameliorated autoimmune diseases in several experimental models, including colitis. However, the mechanism(s) underlying the protective effects of PARP1 inhibition in colitis and the cell types in which Parp1 deletion has the most significant impact are unknown. The objective of the current study was to determine the impact of Parp1 deletion on the innate immune response to mucosal injury and on the gut microbiome composition. Parp1 deficiency was evaluated in DSS-induced colitis in WT, Parp1∼/∼, Rag2∼/∼, and Rag2∼/∼ xParp1∼/∼ double knock-out mice. Genome-wide analysis of the colonic transcriptome and fecal 16S amplicon profiling was performed. Compared with WT, we demonstrated that Parp1 ∼/∼ were protected from dextran-sulfate sodium-induced colitis and that this protection was associated with a dramatic transcriptional reprogramming in the colon. PARP1 deficiency was also associated with a modulation of the colonic microbiota (increases relative abundance of Clostridia clusters IV and XIVa) and a concomitant increase in the frequency of mucosal CD4+CD25+ Foxp3+ regulatory T cells. The protective effects conferred by Parp1 deletion were lost in Rag2∼/∼ X Parp1∼/∼ mice, highlighting the role of the adaptive immune system for full protection.

Original languageEnglish (US)
Pages (from-to)8918-8930
Number of pages13
JournalJournal of Biological Chemistry
Volume291
Issue number17
DOIs
StatePublished - Apr 22 2016

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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