Investigating the Ikaros family of transcription factors within macrophages in inflammatory bowel disease

Sondh, Jagjeet Kaur (2023). Investigating the Ikaros family of transcription factors within macrophages in inflammatory bowel disease. University of Birmingham. Ph.D.

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Abstract

The Ikaros Family of transcription factors Aiolos, Eos, Helios, Ikaros and Pegasus are a family of zinc finger proteins involved in the regulation of genes within a plethora of immune cells. Studies have suggested the family play a role in mediating Regulatory T cell (Treg) and T helper 17 (Th17) responses within Inflammatory Bowel Disease (IBD) but much of the detail of their function and expression is undocumented. This thesis examines the expression and roles of the family in IBD and the associated autoimmune liver disease Primary Sclerosing Cholangitis (PSC). Using qPCR and immunohistochemistry, we investigated the expression of the Ikaros family in blood derived CD4+ T Cells, myeloid cells, and whole bowel and liver tissue from diseased and healthy individuals. I also used an siRNA knockdown of Eos (siEos) within THP- 1 derived macrophages to investigate changes in phenotype and function. We report altered expression of family members within diseased bowel and liver in CD4+ T cells, but also myeloid cells. This includes previously unreported expression of the family within macrophage populations, with changes observed in macrophage subtypes. Ikaros family members were present in both the bowel and liver with greater numbers of Eos and Helios-expressing macrophages found in diseased bowel. Importantly, Eos expression was elevated in monocytes from both Biologic Naïve and anti-TNFalpha treated patient samples in comparison to Control, with novel correlations between Ikaros family members and liver clinical markers also identified. Using siRNA, we found siEos macrophages have reduced phagocytic capacity and upregulated proinflammatory mediator production suggesting Eos promotes a regulatory macrophage phenotype. Together, our results suggest a novel role for the Ikaros family within macrophage phenotype in bowel and liver disease.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):