Huff, L. (2020). Examining the Contribution of the DNA Damage Response to Sepsis Survivor Myelosuppression. Unc Charlotte Electronic Theses And Dissertations.
A large portion of patients who survive sepsis, a life-threatening hyperinflammatory response to infection resulting in organ dysfunction, experience a higher risk of mortality than non-septic patients. Innate immune cells of sepsis survivors exhibit a reduced ability to differentiate into a pro-inflammatory phenotype, and many sepsis survivors are unable to mount an adequate immune response to subsequent infection. Based on evidence that sepsis causes increased production of reactive oxygen (ROS) and nitrogen (RNS) species in innate immune cells, which leads to oxidation and injury to DNA and subsequent up-regulation of the DNA damage response (DDR), and on evidence of interplay between the DDR and the immune response in regulating cellular homeostasis, we proposed that factors involved in the DDR play a mechanistic role in triggering the epigenetic change in innate immune cells that leads to this myelosuppression. We hypothesized that constituents of the DDR play a causal role in initiating the epigenetic changes that occur in myeloid stem and progenitor cells (HSPCs) during sepsis and resulting in the persistent macrophage tolerance during subsequent infection. In a cecal ligation and puncture (CLP) murine model of sepsis, our data indicates that bone marrow derived macrophages (BMDMs) from septic mice demonstrate a reduced ability to exhibit the pro-inflammatory ‘M1’ phenotype, as evidenced by several phenotypic markers including iNOS protein expression, nitric oxide (NO) production, and cell morphology. We have further determined that a specific concentration range of glucose oxidase (GOx), a source of oxidative stress, may mimic this phenotypic hypo-responsiveness in BMDMs and RAW 264.7 cells and cause increased activation of DNA damage response (DDR) factor ATM. These results suggest a role for DDR factors in macrophage immunosuppression in sepsis survivors.
