# Role of AMP-activated protein kinase in bacterial endophthalmitis

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2020 · $383,497

## Abstract

Project Summary
The role of myeloid cells such as neutrophils in providing host defense to microbial infections is well-
established; however, the contribution of monocytes/macrophages (Mϕ) to the pathophysiology of bacterial
endophthalmitis is less clear. Our preliminary studies revealed that Mϕ depletion results in increased
inflammatory mediators at the resolution phase, suggesting their involvement in the resolution of
endophthalmitis. The Mϕ perform multiple tasks, including sensing pathogens, tissue repair, and, in response
to host-derived mediators, they differentiate into distinct functional phenotypes; a feature termed "plasticity".
The "classically activated" Mϕ (M1) produce inflammatory cytokines and nitric oxide, contributing to host tissue
damage. Conversely, the "alternatively activated" Mϕ (M2) mediate tissue repair through the elimination of
damaged cells/tissue and the production of anti-inflammatory molecules to resolve inflammation. Therefore,
understanding the mechanisms governing the phenotypic switch of Mϕ can be utilized to develop novel
therapeutic strategies. Our transcriptome and metabolomics analyses of the bacteria-infected retina directed
us to the identification of adenosine monophosphate-activated protein kinase (AMPK), a metabolic gene, which
modulates the infiltrating myeloid cell phenotype in endophthalmitis. We discovered that mice with global
deletion (knockout) of AMPKα1 (KO) developed severe endophthalmitis and pathology compared to wild type
(WT) mice. Mϕ lacking AMPKα1 maintained a low metabolic state, even in the hyper-inflammatory state. To
precisely examine the role of AMPK in myeloid cells, we induced endophthalmitis in myeloid cell specific KO of
AMPKα1 (LysM-KO) and observed that LysM-KO displayed exacerbated inflammation and reduced retinal
function compared to WT mice, suggesting an essential role of AMPK in myeloid cells in the pathogenesis of
bacterial endophthalmitis. Building on these findings, we propose to test our central hypothesis that AMPK
exerts protective effects in bacterial endophthalmitis by modulating the polarization of infiltrating monocytes/Mϕ
to promote inflammation resolution and that metabolic reprograming is an underlying mechanism of the
monocytes/Mϕ phenotype switch. To test our hypothesis, in Aim 1, we will investigate the mechanisms
underlying reduced AMPK activity in bacterial endophthalmitis by examining the modification of LKB1 via
nitrosylation or chemical adduct formation. Aim 2 tests the hypothesis that AMPKα1 ablation enhances the
activation state of myeloid cells and maintains their proinflammatory (M1) state during the resolution phase of
the disease. In Aim 3, we will decipher the bioenergetic events, regulated by AMPK in Mϕ, that polarize and
maintain their pro-inflammatory nature. The anticipated results of this study will demonstrate that defective
AMPK activity in myeloid cells, mainly in monocytes/M impacts the resolution of endophthalmitis via
regulation ...

## Key facts

- **NIH application ID:** 9899998
- **Project number:** 5R01EY026964-04
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** Ashok Kumar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $383,497
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899998

## Citation

> US National Institutes of Health, RePORTER application 9899998, Role of AMP-activated protein kinase in bacterial endophthalmitis (5R01EY026964-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9899998. Licensed CC0.

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