Interferon regukatory factor 5: a systematic study of macrophage gene regulation

Thesis

Macrophages are multifaceted innate immune cells, able to adapt their phenotype to respond to a myriad of conditions, engaging in tissue-specific functions and mediating either inflammatory or anti-inflammatory responses depending on the encountered stimuli. They conduct key roles in the orchestration of immune responses; from pathogen recognition through sterilising inflammation to resolution and repair. The Udalova laboratory has previously demonstrated that IRF5 promotes a pro- inflammatory macrophage phenotype, leading to the secretion of TNF, IL-12, and IL-23, enhancing Th1/Th17-mediated immune responses, and described the cooperation between IRF5 and the transcription factor RelA, which mediate the production of pro- inflammatory genes. The aim of this thesis is to further characterise the activity of IRF5 in macrophage inflammatory responses. I demonstrate that IRF5 not only regulates the transcription of cytokines and chemokines in response to bacterial stimuli, but also anti-microbial peptides, whilst simultaneously down-regulating homeostatic and resolving macrophage functions. My data also suggests that IRF5 plays a role in enforcing monocyte to macrophage differentiation by up-regulating the transcription of key macrophages markers and repressing dendritic cell identity genes. To further characterise the mechanisms of the inflammatory response mounted by macrophages I used an unbiased approach; combining twenty-three transcription factor ChIP-seq data sets with chromatin accessibility information from ATAC-seq, uncovering RUNX1 as a novel partner of IRF5 that binds co-operatively to clusters of enhancers, which control the transcription of pro-inflammatory genes in a signal-dependent manner. This is the first study demonstrating a critical role for RUNX1 in activity of inflammatory macrophages.

Authors: Khoyratty, T

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Macrophage; IRF5; Transcription
• Subjects: Immunology