Knockout of PARP2 in T cells leads to spontaneous colitis with distinct segmental characteristics in PARP1-deficient mice.

Background and aim: Suppression of poly(ADP-ribose) polymerase (PARP) activity, either PARP1 or PARP2, was proven to be beneficial in experimental colitis. The absence of PARP2 exclusively in T cells (T-PARP2-KO) was also shown recently to exert similar protection. Nevertheless, lower PARP1 expression in the intestines and reduced PARP activity in mononuclear cells from IBD patients were reported. Thus, we would like to investigate the effect of PARP2 deficiency in T cells superimposed on a PARP1 deletion background in the large intestines. Methods: DKO animals were generated from crossbreeding mice bearing single knockouts. The large intestines were examined by histopathology and various immune-based methods (immunohistochemistry, ELISA, and Western blot) to characterize the intestinal alterations through comparison with control and single knockout animals. Results: The DKO animals developed spontaneous intestinal inflammation in both the proximal and distal large intestines, reflected by both histological features and altered levels of the pro-inflammatory cytokine TNFα. In DKO animals, higher density of T cells and increased oxidative-nitrative stress were observed in the intestinal epithelium. Altered expression and activation of intracellular inflammatory signaling transduction proteins were found exclusively in the proximal segments, while the distal large intestines displayed elongated crypts despite the higher activation of caspase-3. The higher ratio of Ki-67-positive cells imply that the increased renewal of enterocytes is attributable to mucosal hyperplasia. Conclusions: PARPs may have essential roles in maintaining the integrity of large intestines, which are closely associated with lymphatic tissues. The combined genetic modification could potentially induce harmful alterations of the mucosa and the associated lymphatic tissue, leading to the occurrence of spontaneous inflammation with certain distinct segmental features.