Macrophages are diverse innate immune cells that are highly influenced by the tissue microenvironment in which they reside. The kidney is a unique niche containing the glomerular and tubulointerstitial compartments with diverse cell types and specialised extracellular matrix. Glomerular kidney disease is characterised by the excess deposition of matrix and loss of filtration barrier integrity, which is accompanied by macrophage accumulation. However, it is unclear how kidney macrophages are maintained or regulated within their tissue specific environment during health. Therefore, in this thesis, I hypothesized that macrophage display diverse responses during homeostasis as well as during local and remote tissue injury as a result of the unique influence of the kidney microenvironment. I discovered that macrophage responses are distinct in the kidneys compared to other tissue sites in the context of local and remote injury, represented by the reductionist approach of LPS administration and the influenza mouse model respectively. Further supporting the hypothesis that macrophages have diverse responses, kidney macrophage subsets examined at steady state were distinct in their dependence on monocyte replenishment. In addition to the prevailing heterogeneity of immune responses by kidney macrophages, novel RNA-sequencing of specific subsets revealed distinct transcriptional profiles of biological pathways associated with basement membrane regulation, which included cell adhesion and extracellular matrix organisation. Confirming the relevance of these associated pathways, macrophage subsets isolated from healthy kidneys express transcripts related to major basement membrane components such as type IV collagen and laminin. Furthermore, the kidney macrophage response is altered in Col4a5 knockout (Alport syndrome) mice, where there is a primary defect in basement membrane assembly. In summary, this thesis provides new insight into features within the kidney microenvironment that may be crucial for regulating macrophage response during health and disease.
Date of Award | 1 Aug 2021 |
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Original language | English |
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Awarding Institution | - The University of Manchester
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Supervisor | Rachel Lennon (Supervisor) & Tracy Hussell (Supervisor) |
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Macrophage response within the unique microenvironment of the kidneys in health and disease
Chew, C. (Author). 1 Aug 2021
Student thesis: Phd