# Cytokine Balance in Rheumatoid Arthritis

> **NIH NIH R01** · HOSPITAL FOR SPECIAL SURGERY · 2022 · $391,600

## Abstract

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-activat...

## Key facts

- **NIH application ID:** 10355665
- **Project number:** 2R01AR050401-16
- **Recipient organization:** HOSPITAL FOR SPECIAL SURGERY
- **Principal Investigator:** Lionel B Ivashkiv
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $391,600
- **Award type:** 2
- **Project period:** 2004-09-10 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10355665

## Citation

> US National Institutes of Health, RePORTER application 10355665, Cytokine Balance in Rheumatoid Arthritis (2R01AR050401-16). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10355665. Licensed CC0.

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