5-Aminoimidazole-4-carboxamide ribonucleoside-mediated adenosine monophosphate-activated protein kinase activation induces protective innate responses in bacterial endophthalmitis.
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.
Department of Ophthalmology/Kresge Eye Institute, Wayne State University, Detroit, MI, USA.
Ajay
A
Kumar
Department of Neurology, Henry Ford Health System, Detroit, MI, USA.
Shailendra
S
Giri
Department of Ophthalmology/Kresge Eye Institute, Wayne State University, Detroit, MI, USA.|Department of Anatomy and Cell Biology, Wayne State University, Detroit, MI, USA.|Department of Immunology and Microbiology, Wayne State University, Detroit, MI, USA.
Ashok
A
Kumar
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000276:immunology*; D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000276:immunology; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D058491:Bacterial Load / Q000187:drug effects; D004195:Disease Models, Animal; D009877:Endophthalmitis / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D005260:Female; D005786:Gene Expression Regulation; D006019:Glycolysis / Q000187:drug effects; D054884:Host-Pathogen Interactions; D007113:Immunity, Innate; D058449:Intravitreal Injections; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D010587:Phagocytosis / Q000187:drug effects; D012160:Retina / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology; D012265:Ribonucleotides / Q000494:pharmacology*; D015398:Signal Transduction; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D013211:Staphylococcus aureus / Q000254:growth & development / Q000472:pathogenicity; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016328:NF-kappa B; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; C548179:Prkaa1 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D000103:Acetyl-CoA Carboxylase; C031143:AICA ribonucleotide