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IL-17 regulates LN stromal cell metabolism and function

Award Number: R01AI148356
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: 01/01/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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IL-17 regulates LN stromal cell metabolism and function - ABSTRACT Th17 cells promote pathology in a variety of autoimmune conditions, and new therapies targeting Th17 cells or IL-17 are proving highly effective. In the healthy state, Th17 cells maintain microbial homeostasis in mucosal sites and are important regulators of extracellular bacterial and fungal pathogens 3. Th17 cells are generated in secondary lymphoid organs (SLO), but their primary effects are usually assessed in peripheral target tissues related to clinical disease manifestations. In SLO, specialized stromal cells called fibroblastic reticular cells (FRC) provide structural support to lymphocytes, including establishment of organized functional cellular niches through production of chemokines and pro-survival cytokines. A less well-appreciated role of FRC is to modulate the adaptive immune response. FRC are required for effective anti-viral responses including antibody (Ab) production, but in turn limit Th1 and CD8 T cell proliferation in response to IFNγ produced by T cells. However, Th17:FRC interactions remain almost entirely unexplored. We now show that IL-17 plays a critical role in expansion and survival of FRC in two distinct model settings: experimental autoimmune encephalomyelitis (EAE) and colitis. Unexpectedly, IL-17 induced metabolic reprogramming of activated FRC and we identified IκBζ as a critical transcriptional coactivator of IL-17-mediated metabolic effects in vitro. Our data furthermore show that IL-17 activation of FRC enhances adaptive immunity: Conditional deletion of IL- 17R on CCL19+FRC resulted in impaired B cell germinal center formation and antibody production. These data inform our central hypothesis that during Th17 inflammation, IL-17 signaling drives successful metabolic reprogramming and expansion of FRC which allows fulminant activation of the adaptive immune response. In this application we propose interrogating the mechanisms by which IL-17 activates the FRC response and the consequent impact on adaptive immunity. More broadly, by using FRC as a model system to interrogate the IL- 17-IκBζ-metabolism pathway and impact on adaptive immunity, we will gain mechanistic insights on known but still poorly-understood functions of IL-17 in autoimmune inflammation, barrier maintenance, infection resistance and wound healing. This knowledge is important to guide future therapeutic strategies based on reducing harmful effects of IL-17 while maintaining beneficial functions. !


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 = -$9,317 )
2025	2023	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	5	4/11/2025	NON-COMPETING CONTINUATION	-$9,317
														Subtotal = -$9,317

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	001	4	9/25/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$3,157
2024	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	3	9/25/2024	NON-COMPETING CONTINUATION	-$3,157
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $445,368 )
2023	2023	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	5	12/8/2022	NON-COMPETING CONTINUATION	$445,368
														Subtotal = $445,368

Issue Date FY: 2022 ( Subtotal = $452,963 )
2022	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	002	4	7/14/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$250,483
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	3	12/7/2021	NON-COMPETING CONTINUATION	$452,166
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	001	3	7/14/2022	NON-COMPETING CONTINUATION	-$249,686
														Subtotal = $452,963

Issue Date FY: 2021 ( Subtotal = $452,166 )
2021	2021	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	2	12/15/2020	NON-COMPETING CONTINUATION	$452,166
														Subtotal = $452,166

Issue Date FY: 2020 ( Subtotal = $452,166 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	1	12/13/2019	NEW	$452,166
														Subtotal = $452,166

Grand Total All Awards = $1,793,346

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IL-17 regulates LN stromal cell metabolism and function

Award Number: R01AI148356

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: 01/01/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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