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Harry et al. Neuroimmunol Neuroinflammation 2020;7:150-65 I http://dx.doi.org/10.20517/2347-8659.2020.07 Page 153

STIMULUS-DRIVEN METABOLIC RE-PROGRAMMING OF MICROGLIA
In a normal “resting” cell, energy demands are addressed with the conversion of glucose to pyruvate with
entry into glycolysis. Pyruvate in the cytosol can be taken up by mitochondria and enters the tricarboxylic
acid (TCA) cycle where it is oxidized to generate ATP. This provides a total energy gain of approximately
36 ATP per one molecule of glucose. In contrast, with hypoxia or anoxia, the cell has the ability to divert
pyruvate away from mitochondria OXPHOS, allowing for ATP generation during low oxygen conditions.
In this case, one glucose molecule will generate two pyruvate molecules that will be converted to lactate
by lactate dehydrogenase in the cytosol [78,79] . While this reaction generates significantly fewer molecules of
+
ATP, glycolysis proceeds due to the production of NAD . While less efficient, a beneficial effect of a shift
to glycolysis is that it can be very quickly induced to meet cellular demands in cells with high glucose
[80]
capacity . The importance of this shift was initially demonstrated in cancer cells in what is known as the
Warburg effect [81,82] . In cancer, malignant cells shift their demand for biosynthetic precursors and energy
change and change their metabolic profile from a relatively low rate of glycolysis and the oxidation of
pyruvate by the TCA cycle. The shift in metabolic profile is characterized by a lower rate of OXPHOS, high
rate of glycolysis, and elevated lactic acid production. The high glycolytic rate induced during the Warburg
effect is driven by the need to meet the increased demand for production of nucleotides and amino acids.
While this effect was initially identified and characterized in cancer cells, a similar ability to utilize such
a metabolic switch has been demonstrated in immune cells to meet increased energy demands when
[1]
responding to infection or injury .
There is now evidence suggesting a role for metabolic reprogramming by mitochondria in the
maintenance and establishment of innate and adaptive immune responses [75,83-96] . Given that immune
cell populations depend on unique effector functions in response to distinct stimuli that often require
production and secretion of high amounts of signaling factors and antimicrobial agents, it follows that
changes in mitochondria function to meet these demands are crucial for efficient response to distinct
contexts [97-101] . It was initially observed that, upon activation, macrophages increase glycolysis and decrease
oxygen consumption [102,103] . It was further demonstrated that macrophage phenotype can be shifted by
reprogramming glucose metabolism [104,105] , which helps meet energy demands required for shifting cell
function and survival [106] .

Under normal conditions, microglia exist in a surveillance phenotype for constant monitoring of the
[94]
parenchyma [107,108] and preferentially rely on oxidative metabolism [90,109,110] . Upon activation by LPS ,
amyloid-b [111] , and iron loading [112,113] , microglia switch their reliance on OXPHOS metabolism [69,110,114,115]
towards glycolytic metabolism to maintain mitochondrial function and ensure cell survival [91,94,95,116] .
Voloboueva et al. showed that, upon stimulation by LPS, BV-2 microglia increased lactate production
[94]
and decreased mitochondria oxygen consumption and ATP production. This shift was reported to be
modulated by mitochondrial glucose-regulated protein 75/mortalin . Exposure to a combination of LPS
[94]
and IFN-g increases nitric oxide formation, glucose consumption, hexokinase activity, glucose-6-phosphate
dehydrogenase activity, phosphofructokinase-1 activity, lactate dehydrogenase activity, and lactate release,
[94]
[69]
suggesting potentiated glycolysis . Similar findings were reported by Orihuela et al. : following LPS, BV2
microglia and primary murine microglia shifted from a primary oxidative metabolic towards glycolytic
metabolism with no evidence of cell death. An increase in microglial mitochondria has been observed with
activation [117,118] , implicating an association with mitochondria biogenesis. Recent studies have suggested
that a shift in glycolysis in microglia is accompanied by an increase in the enzyme PFKFB3, which is
responsible for activation of phosphofructokinase [119] . Additionally, this metabolic shift has been found to
be regulated by the anti-inflammatory cytokine IL-10 for aerobic glycolysis inhibition and OXPHOS [120] .

In a non-classical activation state, macrophages use oxidative metabolism for functions involved in normal
maintenance functions, tissue repair, and wound healing [73,121,122] . In IL-4 stimulated macrophages [M(IL-4)],