The DNA repair enzymes MTH1 and OGG1 as targets to treat inflammation

Sammanfattning: Chronic and acute inflammatory diseases, such as multiple sclerosis (MS), psoriasis and sepsis, account for vast disability and morbidity in the world. Several new immunomodulating treatment alternatives have been developed over the past decades, but there is still an urgent need for new options. Reactive oxygen species (ROS) are tightly bound to inflammation. They can cause oxidized DNA lesions, which are commonly considered to be detrimental. However, these modifications could potentially also constitute an important part of inflammatory signaling. In this thesis, we thus wanted to determine whether inhibition of two DNA repair enzyme, MTH1 and OGG1, could have immunomodulating effects. MTH1 sanitizes the nucleotide pool from oxidized dNTPs and thus prevents oxidized bases, such as oxidized guanine (8-oxoG) from entering the DNA. OGG1 is a DNA glycosylase excising 8-oxoG from the DNA. MTH1 has been described as a promising target for cancer, as many cancers rely on an up-regulation of MTH1 due to elevated ROS pressure, but its role in inflammation has not been investigated. OGG1 was known to be involved in inflammation from before, but this had mainly been validated with knockout models and few inhibitors. Hence, we wanted to investigate novel small-molecule inhibitors of OGG1 and MTH1 for acute and T cell driven inflammation, respectively. In Paper I, we demonstrate an anti-inflammatory effect of the OGG1 inhibitor TH5487 in both in vitro models and an in vivo model of acute pneumonia. We propose that TH5487 prevents OGG1 from binding to 8-oxoG-rich promoter regions of pro-inflammatory genes, further preventing transcription factors from binding to the DNA. We show that the effect is comparable to OGG1 knockout, and that TH5487 has an effect in the pneumonia model both prophylactically and when given after inflammatory stimulation. In preliminary data, we also propose that the effect is comparable to dexamethasone, but without having a T cell suppressing effect, which could be a major advantage in sepsis and pneumonia. In Paper II-III, we show proof-of-concept of MTH1 inhibitors as anti-inflammatory drug candidates in mouse models of psoriasis and MS, respectively. We show that psoriatic tissue from patients have elevated MTH1 levels, and that the inhibitor TH1579 suppresses T cell activation and kills activated T cells by inducing DNA damage, cell cycle arrest and mitotic disruption. We further discovered some new T cell biology findings, proposing that activated T cells exhibit a heterogeneity in MTH1 levels, where a subgroup of T cells can proliferate despite low MTH1 and ROS levels. The toxicity among other immune cells was generally low. Conclusively, we propose these novel inhibitors of the DNA repair enzymes OGG1 and MTH1 to be promising drug candidates for acute and T cell driven inflammation. Other indications, as well as the role of ROS and DNA repair in inflammation, are discussed further in the thesis.