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Title: Tissue-specific control of macrophage phenotype and its relevance to inflammation
Author: Pickering, Robert
ISNI:       0000 0004 7223 7154
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2017
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Tissue resident macrophages are a highly heterogeneous cell type present in every mammalian tissue, where they have a critical role in innate immune defence and tissue homeostasis. Tissue-specific master regulators have been identified in different tissue-resident macrophage populations, which regulate macrophage tissue-specific phenotype and function through the induction and maintenance of specific transcriptional programs. However, it is largely unclear how transcriptional master regulators control tissue-specific macrophage phenotype during the initiation of the inflammatory response and the resolution thereof. Genetic deletion of these tissue-specific transcriptional regulators typically results in the ablation of the specific macrophage populations, such as the loss of splenic red pulp macrophages in of Spi-C deficient mice. Conversely, genetic deletion of Gata6 in macrophages does not completely ablate the population of peritoneal macrophages, albeit it leaves them at reduced numbers. Thus, Gata6-deficient pMφs provide a unique tool to investigate how tissue-specific transcription factors regulate macrophage function during homeostasis and in response to environmental stimuli, such as those encountered during inflammation. As such, the work presented in this thesis aimed to characterise the role that Gata6 has during the inflammatory response of peritoneal macrophages, to identify mechanisms by which it regulates inflammatory processes, and to try and identify whether other GATA family members had analogous roles in other myeloid cells. Several key findings were generated during the studies presented in this thesis. Gata6-deficient macrophages were found to have dysregulated production of TNF, as well as the NLRP3- and caspase-1-dependent release of IL-1β in response to LPS stimulation alone. Interestingly, the aberrant release of pro-inflammatory cytokines from Gata6-deficient pMφs was attenuated by co-culturing with pMφs from Gata6-WT mice, suggesting that Gata6 might release soluble factors that mediate the resolution of inflammation. I identified prostacyclin synthase to be highly expressed in resident pMφs and show that it’s expression was greatly reduced in Gata6-deficient pMφs. Consequently, the production of prostacyclin was severely diminished in Gata6-deficient pMφs following LPS stimulation compared to those from Gata6-WT mice. Treatment of LPS-stimulated Gata6-deficient pMφs with beraprost, a prostacyclin analogue, restored pro-inflammatory cytokine production comparable to pMφs from Gata6-WT mice. The transcription factor GATA3 was found to be selectively up-regulated in Langerhans cells (LCs) generated in vitro from the MUTZ-3 cell line compared to the precursors. However, the knockdown of GATA3 expression with shRNAs did not affect the development, maintenance, or phenotype of LCs in this model.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available