Modulation of neuroinflammation with cargo-less liposomes

Sheikholeslami, Behjat

Modulation of neuroinflammation with cargo-less liposomes

Sheikholeslami, Behjat

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Publication Type:: Thesis
Issue Date:: 2023

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Field	Value	Language
dc.contributor.author	Sheikholeslami, Behjat
dc.date.accessioned	2023-07-13T02:53:11Z
dc.date.available	2023-07-13T02:53:11Z
dc.date.issued	2023
dc.identifier.uri	http://hdl.handle.net/10453/171476
dc.description	University of Technology Sydney. Graduate School of Health.	en_US.UTF-8
dc.description.abstract	An increase in the life span has increased the incidence of a series of age-related neurodegenerative disorders, characterised by progressive neuronal damage and chronic deterioration of CNS psychiatric, cognitive or motor functions. Neuroinflammation is considered a classical feature of neurodegenerative diseases. It represents chronic activation of CNS innate immune cells and enhanced secretion of pro-inflammatory cytokines and neurotoxic mediators that could affect the function of endothelial monolayer and result in neurodegeneration. The benefits and potential therapeutic efficacy of phospholipids in neuroinflammation have been extensively investigated. A phospholipid-based formulation (referred to as UTS-001) has been recently designed in our group that successfully modulated the inflammatory markers in a murine model of allergic airway inflammation and in a murine model of systemic metabolic inflammation. This thesis aimed to study (1) the efficacy of UTS-001 in alleviating brain inflammation in vivo; (2) its effect on activated microglia in vitro; (3) its impact on the blood-brain barrier integrity in vitro; (4) its efficacy in reducing the inflammation of brain endothelium in vitro, and finally (5) the potential of UTS-001 in reducing the peripheral inflammation and (6) the monocytes trafficking into the brain in vitro. Lipopolysaccharide (250 µg/Kg, i.p., seven days) induced systemic inflammation in male C57BL/6 mice. Simultaneous treatment with UTS-001 (i.p., for either 7 or 14 consecutive days) decreased the expression of including interleukin (IL)-1β, tumour necrosis factor (TNF)-α, toll-like receptor (TLR)-4, and inducible nitric oxide synthase (iNOS) and activated macrophages in the brain. In contrast, UTS-001 failed to inhibit the inflammation in LPS-induced microglial cells. UTS-001 did not impact the integrity of the monolayer made up of human cerebral microvascular endothelial cells (hCMEC/D3), while causing a significant reduction in IL-6 and monocyte chemoattractant protein-1 (MCP-1) levels in TNF-α-induced hCMEC/D3 cells. In contrast, it elevated the levels of IL-8 and regulated upon activation, normal T cell expressed and presumably secreted (RANTES). UTS-001 pre-treatment remarkably inhibited the upregulation of IL-8, MCP-1 and RANTES in LPS-stimulated THP-1 cells (human leukemia monocytic cell line used as a model of human monocytes) mainly via inhibition of nuclear factor (NF)-κB signalling pathway. However, it did not impact the transmigration of THP-1 cells through the BBB. Taken together, UTS-001 can alleviate brain inflammation by reducing the inflammatory markers produced by endothelial cells and, notably, by inhibiting the inflammation caused by monocytes. Therefore, UTS-001 has the potential to be further investigated as a therapeutic agent for the treatment of neuroinflammation.	en_US.UTF-8
dc.format	Thesis (PhD)
dc.language.iso	en_US	en_US.UTF-8
dc.relation	https://opus.lib.uts.edu.au/bitstream/10453/171476/1/thesis.pdf
dc.rights	info:eu-repo/semantics/openAccess
dc.rights	The author owns the copyright in this thesis including all reproduction and reuse rights for the work. The work may not be altered without the permission of the copyright owner. Attribution is essential when quoting or paraphrasing from this thesis.
dc.rights	© 2023 Behjat Sheikholeslami
dc.rights	au.edu.uts.lib/cph
dc.title	Modulation of neuroinflammation with cargo-less liposomes	en_US.UTF-8
dc.type	Thesis
utslib.copyright.status	open_access	*

Abstract:

An increase in the life span has increased the incidence of a series of age-related neurodegenerative disorders, characterised by progressive neuronal damage and chronic deterioration of CNS psychiatric, cognitive or motor functions. Neuroinflammation is considered a classical feature of neurodegenerative diseases. It represents chronic activation of CNS innate immune cells and enhanced secretion of pro-inflammatory cytokines and neurotoxic mediators that could affect the function of endothelial monolayer and result in neurodegeneration. The benefits and potential therapeutic efficacy of phospholipids in neuroinflammation have been extensively investigated. A phospholipid-based formulation (referred to as UTS-001) has been recently designed in our group that successfully modulated the inflammatory markers in a murine model of allergic airway inflammation and in a murine model of systemic metabolic inflammation. This thesis aimed to study (1) the efficacy of UTS-001 in alleviating brain inflammation in vivo; (2) its effect on activated microglia in vitro; (3) its impact on the blood-brain barrier integrity in vitro; (4) its efficacy in reducing the inflammation of brain endothelium in vitro, and finally (5) the potential of UTS-001 in reducing the peripheral inflammation and (6) the monocytes trafficking into the brain in vitro. Lipopolysaccharide (250 µg/Kg, i.p., seven days) induced systemic inflammation in male C57BL/6 mice. Simultaneous treatment with UTS-001 (i.p., for either 7 or 14 consecutive days) decreased the expression of including interleukin (IL)-1β, tumour necrosis factor (TNF)-α, toll-like receptor (TLR)-4, and inducible nitric oxide synthase (iNOS) and activated macrophages in the brain. In contrast, UTS-001 failed to inhibit the inflammation in LPS-induced microglial cells. UTS-001 did not impact the integrity of the monolayer made up of human cerebral microvascular endothelial cells (hCMEC/D3), while causing a significant reduction in IL-6 and monocyte chemoattractant protein-1 (MCP-1) levels in TNF-α-induced hCMEC/D3 cells. In contrast, it elevated the levels of IL-8 and regulated upon activation, normal T cell expressed and presumably secreted (RANTES). UTS-001 pre-treatment remarkably inhibited the upregulation of IL-8, MCP-1 and RANTES in LPS-stimulated THP-1 cells (human leukemia monocytic cell line used as a model of human monocytes) mainly via inhibition of nuclear factor (NF)-κB signalling pathway. However, it did not impact the transmigration of THP-1 cells through the BBB. Taken together, UTS-001 can alleviate brain inflammation by reducing the inflammatory markers produced by endothelial cells and, notably, by inhibiting the inflammation caused by monocytes. Therefore, UTS-001 has the potential to be further investigated as a therapeutic agent for the treatment of neuroinflammation.

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http://hdl.handle.net/10453/171476