Transcriptional Reprogramming and Resistance to Colonic Mucosal Injury in Poly(ADP-ribose) Polymerase 1 (PARP1)-deficient Mice

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. 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

Multifaceted Role of PARP-1 in DNA Repair and Inflammation: Pathological and Therapeutic Implications in Cancer and Non-Cancer Diseases

“…PARP-1 is also involved in acute and chronic inflammatory bowel disease (IBD), as in the inflamed colon it induces cell death, activates NF-κB and AP-1, and sustains inflammatory cytokine production [100,101]. The role of PARP in intestinal inflammation is also due to its effects on gut microbioma composition as shown in PARP-1 deficient mice or through its enzymatic inhibition [102,103]. We found that PARP-1 inhibits the differentiation of Foxp3 + regulatory T cells (Treg), which are devoted to control the amplitude and duration of inflammatory/immune responses [104].…”

“…We found that PARP-1 inhibits the differentiation of Foxp3 + regulatory T cells (Treg), which are devoted to control the amplitude and duration of inflammatory/immune responses [104]. PARP-1KO mice express Foxp3 at higher levels and generate more inducible regulatory T cells than wild type cells [104], keeping under control the inflammatory responses induced by dextran sodium sulfate [102]. PARP-1-sustained chronic inflammation is associated with colorectal cancer progression both in mice and humans [90,105].…”

PARP-1 protects against colorectal tumor induction, but promotes inflammation-driven colorectal tumor progression

“…This was illustrated in a study using transgenic PARP-1-deficient mice, which were resistant against the bacterial endotoxin LPS and displayed a markedly reduced expression of NF-κB-dependent proinflammatory genes (17). It has also recently been shown that PARP-1-deficient mice are protected against acute colonic mucosal injury induced by dextran sodium sulfate (DSS) (18). It is established that inflammatory processes, as observed in patients with IBD and in the inflammatory microenvironment in sporadic CRC, are tightly linked to the development and progression of malignant disease (19).…”

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

“…Also, PARP1-deficient mice undergo significant transcriptional reprogramming in the colon, with a protective effect in a model of colitis. Analysis of the transcription response showed that the most common gene ontology (GO) types regulated were proteolysis, protein transport, and localization, suggesting that PARP has other functions besides a direct effect on transcription (254). These observations raise the question of tissue-specific PARP functions.…”