# Novel Regulation and Targeting of Macrophages Metabolism in Neuroinflammatory Disorders

> **NIH NIH R01** · HENRY FORD HEALTH SYSTEM · 2020 · $376,250

## Abstract

ABSTRACT
Myeloid cells play a critical role in CNS demyelination and axonal destruction of multiple sclerosis (MS) and
experimental autoimmune encephalomyelitis (EAE). The early phase of the disease is characterized by the
presence of pathogenic activated macrophages (M1 type), while the recovery phase is associated with
alternatively-activated macrophages (M2 type) which release anti-inflammatory cytokines that resolve the
pathogenic inflammation. Activated M1 macrophages depend on glycolysis to boost biosynthetic pathways to
produce inflammatory mediators. However, anti-inflammatory M2 macrophages rely primarily on mitochondrial
respiration. Adenosine monophosphate-activated protein kinase (AMPK) regulates energy metabolism, and thus
controls the balance between glycolysis and mitochondrial respiration. We reported previously that AMPKα1
knockout (KO) mice develop severe EAE indicating AMPK activation is protective, yet the molecular mechanism
by which AMPK regulates EAE disease progression is not known. AMPKα1-KO macrophages exhibit a hyper-
inflammatory phenotype and have a lower rate of metabolism. AMPKα1-KO macrophages also show glycolysis-
tricarboxylic acid (TCA) cycle remodeling, which results in an imbalance in the levels of the endogenous
metabolites, succinate and itaconate, which regulate pro- and anti-inflammatory macrophage functions,
respectively. Their levels are tightly controlled by succinate dehydrogenase (SDH) and immune responsive gene
1 (IRG1), respectively. We hypothesize that the loss of AMPKα1 remodels the glycolytic-TCA pathway causing
an imbalance in the levels of succinate and itaconate, which promotes an M1 phenotype over an M2 phenotype.
This, in turn, promotes Th17 cells and suppresses T regulatory cells leading to a hyperinflammatory CNS immune
response and CNS tissue damage. To test our hypothesis, we have generated monocyte-specific AMPKα1 KO
and macrophage-specific, constitutively active AMPKα1T172D transgenic mice. In Aim 1, we will examine how the
loss or gain of function of AMPKα1 in macrophages regulates M1 versus M2 macrophage polarization and
consequently, Th17 and Tregs differentiation and disease outcomes. Studies under Aim 2 will elucidate the
mechanism by which the loss of AMPKα1 reprograms glycolysis-TCA metabolism leading to an imbalance of
succinate and itaconate metabolites in macrophages, which in turn, determine the macrophage phenotype. The
proposed study is expected to have a positive impact by elucidating the metabolic regulatory mechanism
responsible for macrophage plasticity during disease and investigating AMPKα1 as a potential therapeutic target
for MS. Our innovative genetic mouse models and precise metabolomics approach will allow us to identify the
apparent rewiring of cellular metabolic pathways specific to AMPKα1 in hyperinflammatory cells. Ultimately, this
process could be exploited to tailor novel therapeutic strategies to resolve or limit autoimmune inflammation in
the CNS.

## Key facts

- **NIH application ID:** 9861217
- **Project number:** 5R01AI144004-02
- **Recipient organization:** HENRY FORD HEALTH SYSTEM
- **Principal Investigator:** SHAILENDRA GIRI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,250
- **Award type:** 5
- **Project period:** 2019-02-04 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9861217

## Citation

> US National Institutes of Health, RePORTER application 9861217, Novel Regulation and Targeting of Macrophages Metabolism in Neuroinflammatory Disorders (5R01AI144004-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9861217. Licensed CC0.

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