Immunometabolic responses of adult and umbilical cord macrophages to stimulation with Mycobacterium tuberculosis or Lipopolysaccharide
Citation:
O Maoldomhnaigh, Cilian, Immunometabolic responses of adult and umbilical cord macrophages to stimulation with Mycobacterium tuberculosis or Lipopolysaccharide, Trinity College Dublin.School of Medicine, 2022Download Item:
CilianOMaoldomhnaigh_17345111.pdf (PhD Thesis) 16.41Mb
Abstract:
Tuberculosis (TB) has been the biggest infectious killer in the world in the last decade
and young children are among the most vulnerable groups. Mycobacterium
tuberculosis (Mtb), the bacteria that causes TB, is phagocytosed by macrophages.
Macrophages can mount an effective immune response and kill the intracellular
bacteria, or, in certain circumstances, the macrophage response is suboptimal and
allows intracellular bacterial growth, causing active TB disease. The Warburg effect,
defined as increased glycolysis and decreased oxidative phosphorylation (OXPHOS),
occurs in murine macrophages following lipopolysaccharide (LPS) stimulation and is
required for activation. It was hypothesised that immunometabolic responses in human
macrophages are different to murine responses and that umbilical cord derived
macrophages have an altered immunometabolic response compared with adult
macrophages, which may make infants and children particularly vulnerable to TB.
The Warburg effect was demonstrated in adult monocyte derived macrophages (MDM)
immediately in response to stimulation with LPS or Mtb. Cord blood MDM however did
not decrease OXPHOS. At 24 hours post stimulation, glycolysis remains elevated in both
adult and cord blood MDM, however LPS stimulated adult MDM have increased
OXPHOS. Cord blood MDM secreted less TNF following Mtb stimulation and more IL-6
following LPS stimulation compared with adult MDM.
The effects of IFN-γ or IL-4 on human macrophage immunometabolic phenotype and
function were investigated. IFN-γ increased glycolysis and OXPHOS and IL-4 resulted in
a marked decline in glycolysis. IFN-γ equalised cord and adult TNF production in
response to Mtb. IL-4 caused a decrease in IL-1β production in both adult and cord
MDM stimulated with Mtb. A consequence of increased glycolysis is an increase in
extracellular lactate. The addition of exogenous lactate was found to have an immediate
effect on metabolism, causing a decrease in glycolysis and an increase in OXPHOS.
Lactate significantly reduced the concentrations of TNF and IL-1β produced by human
macrophages in response to Mtb. In addition, lactate significantly improved bacillary
clearance in human macrophages infected with Mtb.
These data indicate that key differences exist in the kinetics of the immunometabolic
response to stimulation in human macrophages compared with that which is
established in the literature in mice. Furthermore, adult and cord blood macrophages
exhibit distinct immunometabolic function upon stimulation which may underlie their
differential ability to respond to infection. These data may help to inform therapeutic
strategies for host-directed therapies for TB.
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Grant Number
National Children's Research Centre
Author's Homepage:
https://tcdlocalportal.tcd.ie/pls/EnterApex/f?p=800:71:0::::P71_USERNAME:COMAOLDODescription:
APPROVED
Author: O Maoldomhnaigh, Cilian
Advisor:
Basdeo, ShareePublisher:
Trinity College Dublin. School of Medicine. Discipline of Clinical MedicineType of material:
ThesisCollections:
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Full text availableKeywords:
Immunometabolism, Macrophage, umbilical cord blood, warburg, lactateLicences: