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Transcriptional profiling of the inflamed peritoneum

Uceda Fernandez, Javier 2018. Transcriptional profiling of the inflamed peritoneum. PhD Thesis, Cardiff University.
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Interleukin (IL)-6 is a pleiotropic cytokine associated with host defence, resolution of inflammation and chronic disease progression. During acute bacterial peritonitis, mice lacking IL-6 are unable to contain infection and display increased bacterial dissemination. To understand how IL-6 contributes to the local containment of infection, studies established an RNA-sequencing and bioinformatics pipeline to examine the role of the stromal tissue compartment in anti-microbial host defence. Investigations compared the host response to infection during both acute resolving peritoneal inflammation and under an inflammatory situation where pro-fibrotic CD4 T-cells contribute to the immune response. Molecular pathway analysis identified roles for IL-6 acting via the Jak-STAT signalling pathway in iron sequestration, complement regulation, and the control of leukocyte adhesion and activation. For example, stromal IL-6 signalling orchestrated responses relevant to the priming or activation of neutrophils, and infiltrating peritoneal neutrophils from infected Il6-/- mice displayed impaired phagocytic and respiratory burst capabilities. Previously we have shown that the IL-6-mediated expansion of peritoneal interferon (IFN)-g-producing CD4 T-cells (Th1 cells) promotes peritoneal fibrosis in response to recurrent bacterial peritonitis. To mimic this environment, acute resolving inflammation was established in mice receiving ex vivo expanded Th1 cells. The presence of Th1 cells promoted IFN-g-mediated STAT1 signalling in the peritoneum, which altered the expression of genes associated with the homeostatic turnover of extracellular matrix. Importantly, the presence of these cells also rescued the defective antimicrobial activities observed in the membrane of Il6-/- mice. This recovery was associated with a shift in the relative activation of STAT1 over that of STAT3. Taken together, these data provide a novel holistic view of IL-6 signalling in stromal tissue, and highlights the importance of STAT1 and STAT3 in shaping the course of inflammation and the host response to infection.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 21 June 2018
Last Modified: 13 Apr 2021 13:52

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