The pathogenic role of poly(ADP‐ribose) polymerase 1 in experimental colitis (902.11)

Abstract

Poly(ADP‐ribose) polymerases (PARPs), including its most abundant isoform PARP1, catalyzes the transfer of ADP‐ribose units from NAD+ to a number of target proteins. In vivo studies have demonstrated that genetic ablation or pharmacological inhibition of PARP1 ameliorates experimental colitis pathophysiological changes. However, the studies have failed to characterize the mechanism by which PARP1 inhibition is protective in colitis. We evaluated the effect of PARP1 deletion in T cell‐mediated colitis in the following scenarios: adoptive naïve CD4+CD45RBHigh T cell transfer from WT or Parp1‐/‐ mice into Rag2‐/‐ and Rag2‐/‐ x Parp1‐/‐ DKO mice and DSS‐induced colitis in WT, Parp1‐/‐, Rag2‐/‐, and Parp1‐/‐Rag2‐/‐ DKO mice. Compared to WT mice, Parp1‐/‐ mice were protected from DSS‐induced colitis. However, WT and Parp1‐/‐naïve T cells were equally colitogenic in Rag2‐/‐ recipients. DKO mice transferred with WT T cells or treated with DSS showed only marginal improvement. Our preliminary data indicate that Parp1 is dispensable in naïve and effector T‐cells, while Parp1‐/‐ mice are protected from colitis resulting from DSS‐induced epithelial damage. Moreover, the lack of significant protection in T cell transfer or DSS models of colitis in DKO mice suggests a pathogenic role of Parp1 in the innate immune cells and regulatory T cells during colitis.Grant Funding Source: NIH Grant 1K01DK099268‐01