Friday, October 3, 2025 10/3/2025

Cytokine Balance in Rheumatoid Arthritis

Award Number: R01AR050401
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/10/2004
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Cytokine Balance in Rheumatoid Arthritis - Activated synovial macrophages (M[phi]s) are major producers of pathogenic cytokines, and play a key role in RA pathogenesis. The long term goals of this project are to understand mechanisms that regulate the balance between activating and feedback inhibitory signaling pathways that are activated in human M[phi]s by inflammatory factors that drive RA synovitis. An associated goal is to use this knowledge to therapeutically modulate balance and crosstalk between signaling pathways to promote resolution of inflammation. Important activators of RA synovial M[phi]s include autocrine TNF, immune complexes, T cell factors, and damage-associated molecular patterns (DAMPs) generated by tissue damage and cell death. DAMPs that activate Toll-like receptors (TLRs), which are amongst the most potent activators of M[phi]s and inflammatory genes such as TNF, IL6, and IL1B, have emerged as important drivers of RA synovial M[phi] activation. RA synovium contains abundant DAMPs including nucleic acids (NAs) derived from dying cells that activate intracellular RNA and DNA sensors. Interestingly, RA synovium also abundantly expresses molecules that bind NAs and potentiate activation of endosomal NA-sensing TLRs (eTLRs: TLR3/7/8/9). Of the eTLRs, TLR7 and TLR8 are highly expressed in RA synovial macrophages, potently drive inflammatory cytokine production including in RA synovial explants, and have been most closely implicated in pathogenesis of RA and inflammatory arthritis models. Human TLR8 is selectively expressed in myeloid cells and potently drives inflammatory cytokine production, but has been relatively understudied as mouse TLR8 is non-functional; interestingly, BAC-transgenic mice expressing human TLR8 (hTLR8) exhibit increased arthritis associated with erosive synovitis, high TNF, and macrophage infiltration that models RA. In the previous project period we focused on regulation of the balance between activating and feedback inhibitory pathways downstream of TNF and TLR8 in human M[phi]. We found that the balance of TLR8 signaling was shifted towards superinduction of inflammatory genes including TNF and IL6 by CXCL4, which is highly expressed in RA synovium. CXCL4 was previously shown to augment eTLR-mediated IFN and cytokine production in DCs by binding NAs and promoting their delivery to endolysosomal compartments. We identified novel and complementary mechanisms whereby CXCL4 activated signaling and chromatin remodeling in human M[phi]s to boost TLR8 responses. Our overarching hypothesis is that CXCL4 and eTLRs like TLR8 cooperatively activate signaling and epigenetic mechanisms that result in synergistic inflammatory gene activation, and that these mechanisms are operative in activated RA synovial M[phi]s. We propose to investigate mechanisms underlying CXCL4-TLR8 synergy and their pathophysiological implications for inflammatory arthritis. We anticipate our studies will yield insights that can be used to attenuate pathologic M[phi] super-activation while leaving basal TLR responses intact for host defense.


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 = $379,852 )
2025	2025	THE HOSPITAL FOR SPECIAL SURGERY FUND, INC.	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	19	6/2/2025	NON-COMPETING CONTINUATION	$27,412
2025	2025	THE HOSPITAL FOR SPECIAL SURGERY FUND, INC.	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	19	1/16/2025	NON-COMPETING CONTINUATION	$352,440
														Subtotal = $379,852

Issue Date FY: 2024 ( Subtotal = $379,852 )
2024	2024	THE HOSPITAL FOR SPECIAL SURGERY FUND, INC.	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	18	1/18/2024	NON-COMPETING CONTINUATION	$352,440
2024	2024	THE HOSPITAL FOR SPECIAL SURGERY FUND, INC.	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	18	5/31/2024	NON-COMPETING CONTINUATION	$27,412
														Subtotal = $379,852

Issue Date FY: 2023 ( Subtotal = $391,600 )
2023	2023	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	17	2/22/2023	NON-COMPETING CONTINUATION	$39,160
2023	2023	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	17	1/18/2023	NON-COMPETING CONTINUATION	$352,440
														Subtotal = $391,600

Issue Date FY: 2022 ( Subtotal = $391,600 )
2022	2022	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	16	2/11/2022	COMPETING CONTINUATION	$391,600
2022	2020	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	15	6/8/2022	NON-COMPETING CONTINUATION	$0
2022	2020	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	15	2/2/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $391,600

Issue Date FY: 2020 ( Subtotal = $387,200 )
2020	2020	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	15	6/18/2020	NON-COMPETING CONTINUATION	$387,200
														Subtotal = $387,200

Issue Date FY: 2019 ( Subtotal = $387,200 )
2019	2019	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	14	6/13/2019	NON-COMPETING CONTINUATION	$387,200
														Subtotal = $387,200

Issue Date FY: 2018 ( Subtotal = $387,200 )
2018	2018	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	13	6/29/2018	NON-COMPETING CONTINUATION	$387,200
														Subtotal = $387,200

Issue Date FY: 2017 ( Subtotal = $387,200 )
2017	2017	THE HOSPITAL FOR SPECIAL SURGERY FUND INC	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	12	6/19/2017	NON-COMPETING CONTINUATION	$387,200
2017	2014	THE HOSPITAL FOR SPECIAL SURGERY FUND INC	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	12/12/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $387,200

Issue Date FY: 2016 ( Subtotal = $387,200 )
2016	2016	HOSPITAL FOR SPECIAL SURGERY (THE)	525 EAST 71ST STREET, 2ND FLR	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	11	6/24/2016	COMPETING CONTINUATION	$387,200
														Subtotal = $387,200

Issue Date FY: 2014 ( Subtotal = $371,498 )
2014	2014	HOSPITAL FOR SPECIAL SURGERY (THE)	525 EAST 71ST STREET, 2ND FLR	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	6/3/2014	NON-COMPETING CONTINUATION	$371,498
														Subtotal = $371,498

Issue Date FY: 2013 ( Subtotal = $360,126 )
2013	2013	HOSPITAL FOR SPECIAL SURGERY (THE)	525 EAST 71ST STREET, 2ND FLR	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	9	6/17/2013	NON-COMPETING CONTINUATION	$360,126
														Subtotal = $360,126

Issue Date FY: 2012 ( Subtotal = $379,080 )
2012	2012	HOSPITAL FOR SPECIAL SURGERY (THE)	525 EAST 71ST STREET, 2ND FLR	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	6/15/2012	NON-COMPETING CONTINUATION	$379,080
														Subtotal = $379,080

Issue Date FY: 2011 ( Subtotal = $379,080 )
2011	2011	HOSPITAL FOR SPECIAL SURGERY (THE)	525 EAST 71ST STREET, 2ND FLR	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	7	6/17/2011	NON-COMPETING CONTINUATION	$379,080
														Subtotal = $379,080

Issue Date FY: 2010 ( Subtotal = $394,313 )
2010	2010	HOSPITAL FOR SPECIAL SURGERY (THE)	525 EAST 71ST STREET, 2ND FLR	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	7/2/2010	COMPETING CONTINUATION	$394,313
														Subtotal = $394,313

Issue Date FY: 2008 ( Subtotal = $331,223 )
2008	2008	HOSPITAL FOR SPECIAL SURGERY (THE)	525 EAST 71ST STREET, 2ND FLR	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	000	5	6/20/2008	NON-COMPETING CONTINUATION	$331,223
														Subtotal = $331,223

Issue Date FY: 2007 ( Subtotal = $337,982 )
2007	2007	HOSPITAL FOR SPECIAL SURGERY (THE)	525 EAST 71ST STREET, 2ND FLR	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	6/8/2007	NON-COMPETING CONTINUATION	$337,982
														Subtotal = $337,982

Issue Date FY: 2006 ( Subtotal = $348,076 )
2006	2006	HOSPITAL FOR SPECIAL SURGERY (THE)	525 EAST 71ST STREET, 2ND FLR	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	6/30/2006	NON-COMPETING CONTINUATION	$348,076
														Subtotal = $348,076

Issue Date FY: 2005 ( Subtotal = $348,076 )
2005	2005	HOSPITAL FOR SPECIAL SURGERY (THE)	525 EAST 71ST STREET, 2ND FLR	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	7/21/2005	NON-COMPETING CONTINUATION	$348,076
														Subtotal = $348,076

Issue Date FY: 2004 ( Subtotal = $348,076 )
2004	2004	HOSPITAL FOR SPECIAL SURGERY (THE)	525 EAST 71ST STREET, 2ND FLR	NEW YORK	NY	10021	NEW YORK	USA	Indicates awards funded from multiple programs	000	1	9/10/2004	NEW	$348,076
														Subtotal = $348,076

Grand Total All Awards = $7,076,434

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Cytokine Balance in Rheumatoid Arthritis

Award Number: R01AR050401

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/10/2004

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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