Mechanisms Regulating Macrophage Activation and Function during Bacterial Infection and Carcinogenesis
Hardbower, Dana Michelle
Macrophages represent a dynamic and plastic subset of the innate immune system. Macrophage functions include immune surveillance and clearance of pathogens, but they have also been implicated in tumorigenesis. Macrophage activation along the M1 (classical, pro-inflammatory macrophage) to M2 (alternatively activated macrophage) axis is a tightly regulated process. Some pathways that regulate macrophage activation are known, but many uncertainties remain. To address questions related to macrophage activation, we chose the highly prolific human pathogen, Helicobacter pylori. H. pylori infection leads to chronic gastric inflammation and macrophages are an essential component of H. pylori-mediated gastritis. The studies outlined in this dissertation have identified two different proteins that regulate macrophage activation. Epidermal growth factor receptor (EGFR) signaling is an essential component of macrophage activation along both M1 and M2 paradigms. Deletion of Egfr in macrophages results in protection from H. pylori-mediated gastritis due to decreased pro-inflammatory M1 activation. Additionally, loss of EGFR signaling in macrophages protected mice from colitis-associated carcinogenesis, due to decreased M1 and M2 activation, and decreased angiogenesis. Conversely, ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine metabolism, serves to promote immune tolerance within the gastric niche. Loss of ODC in macrophages led to increased M1 macrophage activation and increased pro-inflammatory cytokine production. The enhanced M1 macrophage activation was due to alterations in histone modifications to promote transcription. Overall, this dissertation demonstrates that increased knowledge regarding the regulation of macrophage activation can improve our understanding of macrophage biology in inflammation-mediated diseases.