Inflammation can be an unwanted consequence or cause of debilitating diseases of infectious and non-infectious aetiologies. Sepsis can be a result of an uncontrolled immune response to bacterial infections (including MRSA, E. coli and P. Aeruginosa) or viral infections (including SARS-CoV-2 and Influenza). Immune dysfunction can also cause autoimmune diseases including rheumatoid arthritis, ulcerative colitis and Crohn’s disease. Current anti-inflammatory medications have a number of deficiencies including lack of specificity and undesirable side effects. Herein the potential of Non-ionic surfactant vesicles (NISV) as an anti-inflammatory drug and their mode of action is investigated. NISV were found to have a wide array of anti-inflammatory effects on macrophages in vitro including down-regulation of IL-6, IL-12 and multiple chemokines regardless of whether cells were stimulated with LPS, Poly(I:C) or Pam3csk4. The individual components of NISV, monopalmityol glycerol (MPG), dicetyl phosphate (DCP) and cholesterol) did not replicate the immunomodulatory effects found in macrophages, proving the formulation of NISV is essential for the anti-inflammatory effects. Liposomes were shown to augment LPS and Poly(I:C) stimulation of macrophages, inducing upregulation of pro-inflammatory cytokines including IL-6 and TNF-α, demonstrating that the anti-inflammatory effects of NISV are not a common feature of all vesicular formulations. Transcriptomic analyses showed consistent anti-inflammatory effects, and indicated down-regulation of NF-κB as an important aspect of the anti-inflammatory effects mediated by NISV. Metabolomic analysis show NISV disrupt the Warburg effect by reducing production of itaconate and succinate, indicating anti-inflammatory downstream effects. The mechanism through which NISV down-regulate NF-κB is unknown. However, the NISV’s primary component, MPG, demonstrates structural similarity to the sphingolipid, sphingosine-1-phosphate (S1P). As S1P is an immune mediator that acts through NF-κB, future work should explore the hypothesis that MPG disrupts S1P signalling.
Date of Award | 13 Apr 2022 |
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Original language | English |
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Awarding Institution | - University Of Strathclyde
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Sponsors | University of Strathclyde |
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Supervisor | Craig Roberts (Supervisor) & Gareth Westrop (Supervisor) |
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