The retina is considered to be the most metabolically active tissue in the body. However, the link between energy metabolism and
retinal inflammation, as incited by microbial
infection such as
endophthalmitis, remains unexplored. In this study, using a mouse model of Staphylococcus aureus (SA)
endophthalmitis, we demonstrate that the activity (phosphorylation) of 5'
adenosine monophosphate-activated
protein kinase alpha (AMPKα), a cellular energy sensor and its endogenous substrate;
acetyl-CoA carboxylase is down-regulated in the SA-infected retina. Intravitreal administration of an AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleoside (
AICAR), restored AMPKα and
acetyl-CoA carboxylase phosphorylation.
AICAR treatment reduced both the bacterial burden and intraocular
inflammation in SA-infected eyes by inhibiting
NF-kB and MAP
kinases (p38 and JNK) signalling. The anti-inflammatory effects of
AICAR were diminished in eyes pretreated with
AMPK inhibitor, Compound C. The bioenergetics (Seahorse) analysis of SA-infected microglia and bone marrow-derived macrophages revealed an increase in glycolysis, which was reinstated by
AICAR treatment.
AICAR also reduced the expression of SA-induced glycolytic genes, including
hexokinase 2 and
glucose transporter 1 in microglia, bone marrow-derived macrophages and the mouse retina. Interestingly,
AICAR treatment enhanced the bacterial phagocytic and intracellular killing activities of cultured microglia, macrophages and neutrophils. Furthermore, AMPKα1 global knockout mice exhibited increased susceptibility towards SA
endophthalmitis, as evidenced by increased inflammatory mediators and bacterial burden and reduced
retinal function. Together, these findings provide the first evidence that AMPK activation promotes
retinal innate defence in
endophthalmitis by modulating energy metabolism and that it can be targeted therapeutically to treat
ocular infections.