Feehan, Karen Therese;
(2022)
The role of lung mononuclear phagocytes following the resolution of acute inflammation.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
There is increasing evidence that resolution is not the end of innate-immune mediated responses to infection. This thesis investigates the phenotype and function of lung mononuclear phagocyte populations following the resolution of acute inflammation. Using a mouse model of pneumonia elicited by Streptococcus pneumoniae strain EF3030 we have uncovered that mononuclear phagocytes (Ly6Chi monocytes, alveolar macrophages (AMs), interstitial macrophages (IMs)) repopulate the lung, peaking at day 14 post-infection. Moreover, we have found that post-resolution phase macrophages are enriched for the cellular machinery required for prostaglandin E2 (PGE2) biosynthesis. PGE2 production was associated with a prolonged period of immune modulation in which macrophages are maintained in a tolerogenic state to prevent overt re-activation. In addition to their capacity to produce PGE2, transcriptomics of post-resolution phase AMs (SiglecF+CD64+CD11c+) revealed a significant increase in signal in pathways associated with T cell trafficking and differentiation in the lung. Blockade of prostanoid biosynthesis using naproxen and PGE2 signalling via its EP4 receptor using MF498 resulted in a significant reduction the numbers of Tissue Resident Memory T cells (CD103+CD69+CD49a+) in the lung tissue six weeks after infection; specifically affecting the expression of the important TRM marker CD103. Additionally, TRMs in mice treated with MF498 during post-resolution showed little capacity to respond when exposed to a previously encountered stimulus when compared to vehicle controls. In summary, this thesis presents a novel mechanism in which following classical inflammatory resolution, lung macrophages control the maintenance of tissue resident memory T cells. Our data suggest that T cells traffic to the lung following inflammatory resolution whereby they are exposed to macrophage derived PGE2. This upregulates the expression of CD103, which tethers memory T cells to epithelial cells in the mouse lung thereby maintaining their tissue residency.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The role of lung mononuclear phagocytes following the resolution of acute inflammation |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10142282 |
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