# Deciphering Pathways Driving Inflammatory Fibroblast Effector Functions in RA

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $383,789

## Abstract

In rheumatoid arthritis (RA), joint destruction is mediated by the synovium, which becomes inflamed,
hyperplastic, and infiltrated by leukocytes. Fibroblasts constitute the synovial lining and the stromal network of
the sublining layer. Current therapies for RA reduce disease activity but rarely achieve remission.
Combinations of immunosuppressive biologics result in increased infectious complications limiting their use.
We and others are working toward a distinct approach, namely to target synovial fibroblasts and/or their distinct
pathways to abrogate inflammation independent of targeting leukocytes or inflammatory cytokines. In a
recently published report (Nguyen et al. Immunity 2017) and preliminary data, we illustrate how cytokines like
TNF, IL-1b and IL-17 (primary signals) all can activate fibroblasts to produce an array of inflammatory
cytokines (e.g. IL-6) and chemokines (e.g. CCL2, IL-8) and growth factors (e.g. G-CSF) that highlight the role
of fibroblasts themselves as inflammatory cells in RA. Importantly, we found that to achieve strong and
sustained expression of these inflammatory cytokines, chemokines and growth factors, a critical amplification
loop (secondary signal) is essential. This secondary signal is an autocrine positive feedback loop dependent
on signaling downstream of the leukemia inhibitory factor receptor (LIFR). Silencing this receptor abrogates
fibroblast production of IL-6 and a set of co-expressed inflammatory mediators, regardless of which primary
signal is used to activate the fibroblasts. We hypothesize that the LIFR amplification loop is a critical shared
component of fibroblast activation that may be targeted to abrogate fibroblast mediated inflammation in RA.
 In Aim 1, we define the LIFR positive feedback amplification loop signature by RNA sequencing after
stimulating fibroblasts with a series of potent activators including, TNF, IL-1b, IL-17 and LPS. In Aim 2, we
validate the key genes and products that make up the LIFR positive feedback loop signature using RT-PCR
and protein determinations by ELISA and flow cytometry. To validate key effector functions, we examine the
effects of LIFR deletion or silencing in in vitro functional assays that measure leukocyte recruitment and
survival and other functions. In Aim 3, we assess LIFR amplification loop activity in active human RA and in
TNF and methotrexate inadequate responders to assess if this pathway is a component of ongoing
inflammation in RA. Finally, in Aim 4, we determine if targeting the LIFR amplification loop can be an effective
therapy for inflammatory arthritis in mouse models. Together, these studies provide mechanistic insights into
the pathways utilized by fibroblasts that drive inflammation in RA with implications for treatment.

## Key facts

- **NIH application ID:** 9981633
- **Project number:** 5R01AR073833-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Michael B. Brenner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $383,789
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981633

## Citation

> US National Institutes of Health, RePORTER application 9981633, Deciphering Pathways Driving Inflammatory Fibroblast Effector Functions in RA (5R01AR073833-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9981633. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*