Glycolytic inhibitor 2-deoxyglucose suppresses inflammatory response in innate immune cells and experimental staphylococcal endophthalmitis

Exp Eye Res. 2020 Aug:197:108079. doi: 10.1016/j.exer.2020.108079. Epub 2020 May 23.

Abstract

Previously, we have shown that Staphylococcus (S) aureus induces a glycolytic response in retinal residential (microglia) and infiltrated cells (neutrophils and macrophages) during endophthalmitis. In this study, we sought to investigate the physiological role of glycolysis in bacterial endophthalmitis using a glycolytic inhibitor, 2-deoxyglucose (2DG). Our data showed that 2DG treatment attenuated the inflammatory responses of mouse bone marrow-derived macrophages (BMDM) and neutrophils (BMDN) when challenged with either live or heat-killed S. aureus (HKSA). Among the inflammatory mediators, 2DG caused a significant reduction in levels of cytokines (TNF-α, IL-1β, IL-6) and chemokines (CXCL1 and CXCL2). Western blot analysis of 2DG treated cells showed downregulation of bacterial-induced MEK/ERK pathways. In vivo, intravitreal administration of 2DG both pre- and post-bacterial infection resulted in a significant reduction in intraocular inflammation in C57BL/6 mouse eyes and downregulation of ERK phosphorylation in retinal tissue. Collectively, our study demonstrates that 2DG attenuates inflammatory response in bacterial endophthalmitis and cultured innate immune cells via inhibition of ERK signaling. Thus glycolytic inhibitors in combination with antibiotics could mitigate inflammation-mediated tissue damage in ocular infections.

Keywords: 2DG; Endophthalmitis; Glycolysis; Inflammation; Retina; S. aureus.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites / pharmacology
  • Blotting, Western
  • Deoxyglucose / pharmacology*
  • Disease Models, Animal
  • Endophthalmitis / drug therapy*
  • Endophthalmitis / immunology
  • Endophthalmitis / pathology
  • Enzyme-Linked Immunosorbent Assay
  • Eye Infections, Bacterial / drug therapy*
  • Eye Infections, Bacterial / immunology
  • Eye Infections, Bacterial / pathology
  • Female
  • Glycolysis / drug effects
  • Immunity, Innate / drug effects*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Staphylococcal Infections / drug therapy*
  • Staphylococcal Infections / immunology
  • Staphylococcal Infections / pathology

Substances

  • Antimetabolites
  • Deoxyglucose