Tuesday, December 16, 2025 12/16/2025

The role of TNFR2 in ameliorating progressive encephalomyelitis

Award Number: R01NS117742
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: 02/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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The role of TNFR2 in ameliorating progressive encephalomyelitis - The mechanisms driving progressive multiple sclerosis (MS) remain enigmatic. Progression of MS correlates with the expression of the cytokine tumor necrosis factor (TNF) in cerebrospinal fluid of patients, suggesting that TNF plays a key role in the disease process. Thus, targeting TNF was suggested as an attractive therapy for MS. Surprisingly, however, TNF-blocking drugs with proven efficacy in other autoimmune diseases triggered onset and exacerbations of MS, which provided evidence that TNF can also contribute to CNS protection and repair. Subsequent work showed that pathogenic TNF effects in EAE are mediated via TNF receptor (TNFR) 1, whereas TNFR2 signaling ameliorates disease and reduces demyelination. TNFR2 is expressed by different cell types in the CNS, including microglia and oligodendrocytes, and its expression by these cells can promote repair and remyelination. Likewise, astrocytes can express TNFR2, but the role of TNFR2 expressed by astrocytes for MS/EAE progression remains unresolved. Astrocytes with pathogenic (A1) or neuroprotective/anti-inflammatory properties (A2) have been described; however, the mechanisms orchestrating detrimental versus beneficial astrocyte functions are still not fully understood. We have obtained exciting preliminary results supporting a central role for astrocyte TNFR2 in curtailing EAE progression by investigating the role of TNFR2 in a “humanized” transgenic mouse model expressing the human MS-associated MHC II allele HLA-DR2b and lacking the expression of TNFR2 molecules, herein called DR2bΔR2 mice. This model provided evidence that the HLA- DR2b molecule favored Th17 development, while impairing Foxp3+ Treg cell formation. Importantly, we observed that DR2bΔR2 mice developed progressive EAE and astrogliosis when CNS resident cells were TNFR2 deficient. Moreover, in DR2bΔR2 animals with EAE, astrocytes showed increased expression of pro-inflammatory cytokines and increased expression of CXCR5. Additionally, CXCL13 was upregulated in the CNS of these mice in line with previous reports that CNS expression of CXCL13 aggravates EAE and promotes chronic white matter lesions that is not dependent on recruitment of CXCR5+ leukocytes from the periphery, and that CXCL13 expressed by damaged neurons can activate astrocytes. Moreover, we observed a striking dichotomy in the expression of TNFR2 between astrocyte populations in DR2b mice with EAE, suggesting that TNFR2 expression may favor astrocyte A2 versus A1 subpopulations. Thus, our proposal will test the central hypothesis that TNFR2 signaling in astrocytes curtails progression of neuroinflammation by restraining pathogenic and promoting protective astrocyte functions. We will test our hypothesis by (1) determining the role of TNFR2 for curtailing pathogenic astrocyte effector functions and preventing EAE progression; and (2) determining the role of TNFR2-regulated CXCL13/CXCR5 signaling for chronic astrocyte activation and function in progressive EAE in DR2bΔR2 mice. We will accomplish the objectives of this proposal by applying innovative new approaches including our progressive EAE model, developing astrocyte-specific TNFR2 and CXCR5 knockout mice, and innovative immunological and molecular biological methods, including single-cell RNA-seq and RNAScope.


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: 2026 ( Subtotal = $0 )
2026	2025	THE UNIVERSITY OF TEXAS AT SAN ANTONIO	1 UTSA CIR	SAN ANTONIO	TX	78249	BEXAR	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	10/27/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $337,715 )
2025	2025	THE UNIVERSITY OF TEXAS AT SAN ANTONIO	1 UTSA CIR	SAN ANTONIO	TX	78249	BEXAR	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/1/2025	NON-COMPETING CONTINUATION	$337,715
														Subtotal = $337,715

Issue Date FY: 2024 ( Subtotal = $365,906 )
2024	2024	UNIVERSITY OF TEXAS AT SAN ANTONIO, THE	1 UTSA CIRCLE	SAN ANTONIO	TX	78249	BEXAR	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/28/2023	NON-COMPETING CONTINUATION	$339,501
2024	2024	THE UNIVERSITY OF TEXAS AT SAN ANTONIO	1 UTSA CIR	SAN ANTONIO	TX	78249	BEXAR	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	5/3/2024	NON-COMPETING CONTINUATION	$26,405
														Subtotal = $365,906

Issue Date FY: 2023 ( Subtotal = $378,743 )
2023	2023	UNIVERSITY OF TEXAS AT SAN ANTONIO, THE	1 UTSA CIRCLE	SAN ANTONIO	TX	78249	BEXAR	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	2/1/2023	NON-COMPETING CONTINUATION	$37,874
2023	2023	UNIVERSITY OF TEXAS AT SAN ANTONIO, THE	1 UTSA CIRCLE	SAN ANTONIO	TX	78249	BEXAR	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/27/2022	NON-COMPETING CONTINUATION	$340,869
														Subtotal = $378,743

Issue Date FY: 2022 ( Subtotal = $378,743 )
2022	2022	UNIVERSITY OF TEXAS AT SAN ANTONIO, THE	1 UTSA CIRCLE	SAN ANTONIO	TX	78249	BEXAR	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	4/12/2022	NON-COMPETING CONTINUATION	$37,875
2022	2022	UNIVERSITY OF TEXAS AT SAN ANTONIO, THE	1 UTSA CIRCLE	SAN ANTONIO	TX	78249	BEXAR	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/20/2021	NON-COMPETING CONTINUATION	$340,868
														Subtotal = $378,743

Issue Date FY: 2021 ( Subtotal = $378,743 )
2021	2021	UNIVERSITY OF TEXAS AT SAN ANTONIO, THE	1 UTSA CIRCLE	SAN ANTONIO	TX	78249	BEXAR	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/22/2021	NEW	$378,743
														Subtotal = $378,743

Grand Total All Awards = $1,839,850

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The role of TNFR2 in ameliorating progressive encephalomyelitis

Award Number: R01NS117742

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: 02/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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