# Defining the mitochondrial metabolic regulation of systemic innate inflammation

> **NIH NIH R35** · UNIVERSITY OF TENNESSEE KNOXVILLE · 2024 · $364,783

## Abstract

PROJECT ABSTRACT
The interplay between metabolic and inflammatory processes is critical to maintaining overall health where a
delicate balance exists between pathogen clearance and limiting host tissue damage. Severe bacterial infections
upset this equilibrium and lead to a critical condition known as septicemia, where metabolic and immunologic
dysregulation rapidly overwhelms the body’s defenses and poses a life-threatening challenge. Neutrophils are
crucial in establishing innate immunity and undergo an enigmatic cell death process termed neutrophil
extracellular trap (NET) formation (NETosis) that elicits antimicrobial activities but also induces collateral damage
to host tissues during sepsis. We aim to investigate the intricate mechanisms underlying NETosis and how
shifts in metabolic homeostasis during septicemia antagonize NET formation thereby causing aberrant
inflammation. We previously demonstrated that mitochondrial superoxide production promotes downstream
NETosis, and preliminary data indicate a critical role for lactate in this cascade. My research program aims to
determine (i) how excess lactate during bacterial septicemia antagonizes NETosis and the impact this has on
disease outcome. This study reframes mitochondria as ‘sensory organelles’ within neutrophils that respond to
perturbations in the metabolic environment and dictate downstream inflammatory responses rather than acting
as the ‘powerhouse’ of the cell. These metabolic shifts during sepsis may play a direct role in modulating innate
immunity and (ii) we aim to understand how hyperglycemia and increased lactate availability during septicemia
influence lactylation of histones and downstream gene expression in neutrophils. These studies are aided by our
discovery of a biomarker that transiently accumulates on the surface of neutrophils that accurately predicts
neutrophils that will undergo NETosis 2-3 hr later, which will allow us to decipher transcriptional changes related
to NETosis and contrast transcriptomes across different biologically and clinically relevant bacterial inducers of
sepsis in various tissues during septicemia. While much of this proposal focuses on the impacts of glucose and
lactate and inflammation, the complex metabolic environment during sepsis likely has diverse effects on innate
immunity in differing tissues. Therefore, (iii) we will employ chimeric immune cell editing (CHIME) using small
CRISPR-based libraries to target 40-50 metabolic genes so that each neutrophil in a mouse has a single gene
disrupted. This technology will allow us to decipher the metabolic dependencies driving neutrophil recruitment
and inflammatory processes across differing tissues or in response to common bacterial pathogens associated
with sepsis. These studies are significant as they begin to unravel the mechanistic links between metabolic and
transcriptional dysregulation during sepsis and the impact this has in skewing innate immunity of neutrophils to
combat the invadin...

## Key facts

- **NIH application ID:** 10937800
- **Project number:** 1R35GM154838-01
- **Recipient organization:** UNIVERSITY OF TENNESSEE KNOXVILLE
- **Principal Investigator:** Andrew J Monteith
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $364,783
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10937800

## Citation

> US National Institutes of Health, RePORTER application 10937800, Defining the mitochondrial metabolic regulation of systemic innate inflammation (1R35GM154838-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10937800. Licensed CC0.

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