Interplay between innate epithelial sensing and mucosal immunity

Scarfe, Lisa ORCID: https://orcid.org/0000-0002-7769-2346 (2024). Interplay between innate epithelial sensing and mucosal immunity. University of Birmingham. Ph.D.

Preview

Scarfe2024PhD.pdf
Text - Accepted Version
Available under License All rights reserved.
Download (8MB) | Preview

Abstract

Maintenance of intestinal integrity is dependent on crosstalk between epithelial, stromal and immune cells and the gut microbiota. Nod-like receptor (NLR) apoptosis inhibitory proteins (Naips) activate the NLRC4 inflammasome upon recognition of gram-negative bacteria, leading to pyroptosis/apoptosis, intestinal epithelial cell expulsion and release of IL-1β, IL-18 and prostaglandin E2 (PGE2). NAIPs also appear to have homeostatic roles within the intestinal epithelium, as our group has previously shown that Naips suppress colonic tumourigenesis but enhancecolonic inflammation. We aimed to further understand the role of Naips on the immune compartment in inflammatory disease, usingmodels of colorectal cancer and Salmonella infection. Following Salmonella infection, ice lacking epithelial Naips (NaipΔ/Δ) had increased numbers of TCRαβCD8αα and TCRγδ+ intraepithelial lymphocytes, which was not caused by increased bacterial burden. Using colonic organoids, we identified increased IL-15/IL-15R in NaipΔ/Δ and altered basal levels of eicosanoids (PGF2α and 17,18-DiHETE) with altered expression of eicosanoid-related genes. However, organoid co-cultures suggested neither explained the increase in intraepithelial lymphocytes, with further work needed to elucidate the mechanism behind this. Following colorectal cancer induction, only slight differences were seen in the tumour infiltrating lymphocytes of NaipΔ/Δ mice compared to Naipfl/fl, though there was a trend towards decreased conventional CD4+ T cells and an increase in TCRγδ cells. However, NaipΔ/Δ cancer-derived organoids increased MHCII expression in response to IFNγ, whereas Naipfl/fl did not. This was not explained by differences in IFNγ signalling or prostaglandin production. Further investigation is needed to determine the exact role of Naips in colorectal cancer and why NaipΔ/Δ mice experience increased tumorigenesis.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):