Abstract
Poly-ADP-ribose polymerases (PARPs) are important regulators of the immune system, including TCDD-inducible poly-ADP-ribose polymerase (TIPARP), also known as poly-ADP-ribose polymerase 7 (PARP7). PARP7 negatively regulates aryl hydrocarbon receptor (AHR) and type I interferon (IFN-I) signaling, both of which have been implicated in intestinal homeostasis and immunity. Since the loss of PARP7 expression increases AHR and IFN-I signaling, we used a murine dextran sulfate sodium (DSS)-induced colitis model to investigate the effect of PARP7 loss on DSS-induced intestinal inflammation. DSS-exposed Parp7−/− mice had less body weight loss, lower disease index scores, and reduced expression of several inflammation genes, including interleukin IL-6, C-x-c motif chemokine ligand 1 (Cxcl1), and lipocalin-2, when compared with wild-type mice. However, no significant difference was observed between genotypes in the colonic expression of the AHR target gene cytochrome P450 1A1 (Cyp1a1). Moreover, no significant differences in microbial composition were observed between the genotypes. Our findings demonstrate that the absence of PARP7 protein results in an impaired immune response to colonic inflammation and suggests that PARP7 may participate in the recruitment of immune cells to the inflammation site, which may be due to its role in IFN-I signaling rather than AHR signaling.
Highlights
Post-transcriptional modifications, such as phosphorylation, ubiquitination, and ADPribosylation, allow for the fast and efficient integration of different stimuli during an infection and are important in controlling immune responses
The mechanisms are unknown, our findings suggest that poly-ADP-ribose polymerase 7 (PARP7) may be a potential new therapeutic target for Inflammatory bowel disease (IBD)
PARP7 functions as part of a negative feedback loop that regulates aryl hydrocarbon receptor (AHR) signaling and protects against TCDD toxicity [9,19]. It is not known whether endogenous or dietary AHR ligands increase AHR signaling in the absence of PARP7 expression
Summary
Post-transcriptional modifications, such as phosphorylation, ubiquitination, and ADPribosylation, allow for the fast and efficient integration of different stimuli during an infection and are important in controlling immune responses. AHR enters the nucleus where it heterodimerizes with AHR nuclear translocator (ARNT) This complex binds to AHR response elements in the regulatory regions of its target genes, including the drug-metabolizing enzymes cytochrome P450 1A1 (CYP1A1) and CYP1B1, PARP7, cytokines, growth factors, and cell cycle regulators [29]. AHR activation significantly improves, while its loss exacerbates, dextran sodium sulphate (DSS)-induced colitis, a model of IBD [30,31,32] This is due to the loss of anti-inflammatory intestinal type 3 innate lymphoid (ILC3) cells, decreased barrier integrity, and dysregulated intestinal inflammation [28,30]. IFN-I signalling suppresses enteric viral and intestinal bacterial infections, but it reduces the severity of DSS-induced colitis in mice and inhibits pro-inflammatory cytokine production in tissues isolated from patients suffering from UC [34,35]. The mechanisms are unknown, our findings suggest that PARP7 may be a potential new therapeutic target for IBD
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