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Endogenous metabolite restricts GM-CSF signaling pathway in pathogenic macrophages to ameliorate CNS Autoimmunity

Award Number: R01NS112727
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Endogenous metabolite restricts GM-CSF signaling pathway in pathogenic macrophages to ameliorate CNS Autoimmunity - ABSTRACT Identifying a therapeutic option that can modulate the innate immune response without generally suppressing the immune system as a whole has been a key barrier to improving treatment for patients with MS. Using metabolic profiling, we have reported that resolvin D1 (RvD1), a pro-resolving lipid metabolite of omega-3 polyunsaturated fatty acids, is significantly decreased in the plasma of patients with MS. Consistent with this finding, MS patients have lower levels of omega-3 metabolites, which are precursors of resolvins, compared to healthy controls, a finding that has been replicated in animal models of the disease, experimental autoimmune encephalomyelitis (EAE). Notably, we found that daily supplementation with RvD1 significantly attenuated clini- cal symptoms in both chronic and relapsing-remitting EAE. These data are provocative for their translational potential, particularly because the immune system is not depressed by RvD1 treatment as it is with steroids and most other MS therapies. The immunomodulatory effect of RvD1 is mediated through its receptor, formyl peptide receptor 2 (FPR2), leading to modulation of AMP-activated protein kinase (AMPK), an important regulator of cell metabolism. In other human disease models, the RvD1-FPR2 signaling cascade protects by inducing an anti- inflammatory phenotype in macrophages. However, the mechanism affording this protection remains elusive. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a key player both in the pathology of both MS and EAE, promotes an inflammatory environment and neuronal damage. There is a growing interest in inhibiting the pro-inflammatory effects of GM-CSF signaling as a therapeutic target in MS. In our preliminary work, we found that RvD1 treatment inhibited GM-CSF signaling in macrophages and that this inhibition was AMPK de- pendent. However, how RvD1 affects AMPK activity and GM-CSF signaling to attenuate EAE is unclear. Our long-term goal is to identify natural endogenous signaling mechanisms that can be harnessed to treat autoim- mune diseases, particularly MS. Our overall objective here is to determine the mechanism of action of RvD1 in resolving inflammation and disability in mouse models of MS. Our central hypothesis is that RvD1 attenuates EAE disease progression by abrogating GM-CSF signaling resulting in the polarizing of pro-inflammatory mac- rophages into an anti-inflammatory phenotype. And the underlying mechanisms of macrophage phenotype switch are through FPR2-AMPK-dependent metabolic reprogramming. To test this hypothesis our specific aims are: 1) to identify the effects of RvD1 on the cellular phenotype and function of CNS-infiltrating macro- phages in EAE; and 2) to determine the effects of RvD1 on metabolic reprogramming in macrophages. We will address these aims with a combination of immunological, biochemical and innovative metabolomic ap- proaches that are already well in hand. The proposed studies will form the foundation for the development of innovative therapeutic strategies to resolve inflammation during MS with no side effects and will likely apply to other diseases involving pathogenic activation of the immune system.


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 # 5B	DETROIT	MI	48202	WAYNE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	8/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $329,219 )
2023	2023	HENRY FORD HEALTH SYSTEM	1 FORD PL	DETROIT	MI	48202	WAYNE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/17/2023	NON-COMPETING CONTINUATION	$329,219
														Subtotal = $329,219

Issue Date FY: 2022 ( Subtotal = $329,219 )
2022	2022	HENRY FORD HEALTH SYSTEM	1 FORD PLACE	DETROIT	MI	48202	WAYNE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/31/2022	NON-COMPETING CONTINUATION	$329,219
														Subtotal = $329,219

Issue Date FY: 2021 ( Subtotal = $329,219 )
2021	2021	HENRY FORD HEALTH SYSTEM	1 FORD PLACE	DETROIT	MI	48202	WAYNE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/10/2021	NON-COMPETING CONTINUATION	$329,219
														Subtotal = $329,219

Issue Date FY: 2020 ( Subtotal = $329,219 )
2020	2020	HENRY FORD HEALTH SYSTEM	1 FORD PLACE	DETROIT	MI	48202	WAYNE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/12/2020	NON-COMPETING CONTINUATION	$329,219
														Subtotal = $329,219

Issue Date FY: 2019 ( Subtotal = $329,219 )
2019	2019	HENRY FORD HEALTH SYSTEM	1 FORD PLACE	DETROIT	MI	48202	WAYNE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/13/2019	NEW	$329,219
														Subtotal = $329,219

Grand Total All Awards = $1,646,095

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Endogenous metabolite restricts GM-CSF signaling pathway in pathogenic macrophages to ameliorate CNS Autoimmunity

Award Number: R01NS112727

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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