Spelling suggestions: "subject:"macrophages biology""
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The voltage-gated proton channel HVCN1 modulates mitochondrial ROS production and inflammatory response in macrophagesEmami-Shahri, Nia January 2014 (has links)
It is clear that the voltage-gated proton channel HVCN1 plays an essential role in a range of cell types, in particular immune cells. Previous published work has confirmed the existence of proton channels in both murine and human macrophages. However, the role of HVCN1 in macrophages has not been investigated. Given that the current literature on voltage-gated proton channels in immune cells has found HVCN1 to be involved in several cellular processes (such as the respiratory burst and signalling events) it is important to establish its functional role in macrophages, which are a crucial constituent of the immune system. The aim of my thesis was to investigate the function of voltage-gated proton channels in macrophages with the use of mice with a disrupting mutation within the Hvcn1 gene, which results in HVCN1 loss. In particular, I wanted to address how Hvcn1-/- macrophages responded to LPS activation. I hypothesised that HVCN1 regulates the respiratory burst of macrophages and that it potentially modulates mitochondrial ROS production, and in doing so, may affect several functional aspects of macrophage biology.
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Myeloid AMPK in Atherosclerosis: Therapeutic Potential and Associated MechanismsLeBlond, Nicholas 13 October 2020 (has links)
Atherosclerosis propagates when innate immune cells, myeloid-derived macrophages, undergo unregulated uptake of cholesterol-rich modified low-density lipoproteins (LDL). Excess storage and retention of this cholesterol leads to development of lipid-laden macrophage foam cells, that accumulate within the intima of arteries as developing plaque. Formation of atherosclerotic lesions reduces blood flow and can further lead to more serious complications such as myocardial infarction, stroke, and cardiovascular disease. AMP-activated protein kinase (AMPK), a master regulator of cellular energetics, has been shown to participate in many anti-atherogenic pathways within myeloid cells such as (but not limited to) the inhibition of cholesterol synthesis and stimulation of reverse cholesterol transport. However, a recent report described a pro-atherogenic role for myeloid AMPK, showing it is expression required for myeloid cell recruitment and longevity within the atherosclerotic microenvironment. Despite this, multiple reports all corroborate describing a protective role for systemic pharmacological AMPK activation. We sought to determine the consequence of modified LDL variants in myeloid AMPK signaling and to further clarify the role of myeloid AMPK signaling within atherosclerosis. In cultured macrophages primed with modified LDL variants underwent AMPK activation, which was also associated with increased markers of autophagy. In an in vivo model of intermediate atherosclerosis, we observed that neither myeloid AMPK expression nor systemic AMPK-activating therapy influenced lesion myeloid content, necrosis, or autophagic markers. Furthermore, despite a suggestive trend, both myeloid AMPK and AMPK-therapy did not significantly influence lesion size in male or female mice. Interestingly, we found that in animals lacking AMPK signaling to only one substrate, HMGCR (the rate limiting enzyme in cholesterol synthesis), knock-in mice developed accelerated atherosclerosis when compared to their wild-type littermate. Furthermore, we determined that AMPK signaling to HMGCR in the hematopoietic compartment alone is enough to protect against atherogenesis. Taken together, these studies show the benefit of interrogating specific AMPK-regulated pathways in the context of atherosclerosis, and sheds light on the benefit of utilization of single point mutation knock-in models opposed to global or cell type-specific knockout models for investigations into AMPK within atherosclerosis.
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Secretion from the Leishmania flagellum as a potential mechanism of virulence factor deliveryMakin, Laura January 2017 (has links)
Protozoa of the Leishmania genus are transmitted between mammalian hosts by the sandfly and cause the neglected tropical disease leishmaniasis. Upon injection into the mammalian host by the sandfly promastigote-form parasites are phagocytosed by macrophages, where they differentiate into amastigotes. Although many virulence factors are known to modulate macrophage signalling pathways to favour infection, the delivery mechanisms are largely unknown. During differentiation to amastigotes the promastigote flagellum shortens dramatically and the fate of the excess flagellar membrane is unknown. Here we investigate the possibility that during Leishmania mexicana differentiation, shedding of the flagellar membrane is a source of extracellular vesicles (EVs) which provide a virulence factor delivery mechanism. The kinetics and structural mechanisms of EV release from promastigotes were investigated by live cell imaging and by measuring the concentration of shed EVs. Isolated EVs from a differentiating parasite culture or a control promastigote parasite culture were analysed by fluorescence and electron microscopy and mass spectrometry. To study the biological effects of EVs, macrophages were exposed to isolated EVs or live promastigotes and cytokine secretion was quantified by ELISA. An LPG1 null mutant was used to assess the contribution of virulence factor lipophosphoglycan (LPG) to the observed effects. Known protein virulence factors and LPG are present in L. mexicana EV fractions as well as known flagellar proteins. We show that there is a link between L. mexicana flagellar shortening and EV release, which is a recently discovered phenomenon in Chlamydomonas and mammalian cell research. We find that isolated EVs and live promastigotes induce changes in secreted cytokine levels from human and murine macrophages, including a substantial and previously unreported suppression of CXCL10, a chemokine which plays a protective role in Leishmania infection. LPG contributes to the effects observed on cytokine production, and EVs may be an important delivery mechanism for LPG.
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