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Novel Regulation and Targeting of Macrophages Metabolism in Neuroinflammatory Disorders

Award Number: R01AI144004
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/04/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Novel Regulation and Targeting of Macrophages Metabolism in Neuroinflammatory Disorders - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	HENRY FORD HEALTH SYSTEM	1 FORD PL	DETROIT	MI	48202	WAYNE	USA	Allergy and Infectious Diseases Research	000	5	6/6/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $376,250 )
2023	2023	HENRY FORD HEALTH SYSTEM	1 FORD PL	DETROIT	MI	48202	WAYNE	USA	Allergy and Infectious Diseases Research	000	5	1/12/2023	NON-COMPETING CONTINUATION	$376,250
														Subtotal = $376,250

Issue Date FY: 2022 ( Subtotal = $389,213 )
2022	2022	HENRY FORD HEALTH SYSTEM	1 FORD PLACE	DETROIT	MI	48202	WAYNE	USA	Allergy and Infectious Diseases Research	000	4	1/25/2022	NON-COMPETING CONTINUATION	$389,213
														Subtotal = $389,213

Issue Date FY: 2021 ( Subtotal = $421,610 )
2021	2021	HENRY FORD HEALTH SYSTEM	1 FORD PLACE	DETROIT	MI	48202	WAYNE	USA	Allergy and Infectious Diseases Research	001	3	8/19/2021	NON-COMPETING CONTINUATION	$45,360
2021	2021	HENRY FORD HEALTH SYSTEM	1 FORD PLACE	DETROIT	MI	48202	WAYNE	USA	Allergy and Infectious Diseases Research	000	3	1/19/2021	NON-COMPETING CONTINUATION	$376,250
														Subtotal = $421,610

Issue Date FY: 2020 ( Subtotal = $376,250 )
2020	2020	HENRY FORD HEALTH SYSTEM	1 FORD PLACE	DETROIT	MI	48202	WAYNE	USA	Allergy and Infectious Diseases Research	000	2	1/16/2020	NON-COMPETING CONTINUATION	$376,250
														Subtotal = $376,250

Issue Date FY: 2019 ( Subtotal = $376,250 )
2019	2019	HENRY FORD HEALTH SYSTEM	1 FORD PLACE	DETROIT	MI	48202	WAYNE	USA	Allergy and Infectious Diseases Research	000	1	2/4/2019	NEW	$376,250
														Subtotal = $376,250

Grand Total All Awards = $1,939,573

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Novel Regulation and Targeting of Macrophages Metabolism in Neuroinflammatory Disorders

Award Number: R01AI144004

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/04/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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