Circadian Clock Control of Macrophage FunctionCircadian Clock Control of Macrophage Function

UoM administered thesis: Phd

Abstract

The outcome after bacterial infections vary according the time of infectious inoculation. However, the mechanisms underlying this effect remains undefined. Here I show that loss of the core clock protein BMAL1 in macrophages surprisingly confers protection against pneumococcal pneumonia, a prevalent infectious disease. In vivo studies of macrophage phagocytosis showed increased bacterial ingestion following BMAL1 deletion, which was also seen in vitro, but there was no phagocytosis phenotype in neutrophils. The phagocytosis effect was not replicated with disruption, or loss of REVERBα, a clock component, and BMAL1 target gene, previously identified as important for circadian control of inflammation. Bmal1-/- macrophages showed marked differences in their actin cytoskeleton organisation, reduced phospho-cofilin and increased active RhoA. Subsequent phagocytosis assays in the presence of a RhoA inhibitor normalised phagocytosis in BMAL1-/- macrophages to the level of control mice. I show a surprising gain of anti-bacterial function through loss of BMAL1 in macrophages. REVERBα, previously found to be an essential link in clock control of inflammation, is not involved in macrophage phagocytosis. RhoA is identified as a BMAL1 target in macrophages, and is thus an essential link between BMAL1 and macrophage phagocytosis.

Details

Original languageEnglish
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Award date1 Aug 2019