# Macrophages in human autoimmune tissue pathology

> **NIH NIH R01** · HOSPITAL FOR SPECIAL SURGERY · 2020 · $445,000

## Abstract

In the autoimmune condition rheumatoid arthritis (RA), chronic inflammation reshapes cellular interactions and
tissue architecture in patient joints. RA synovium is marked by expanded macrophage and fibroblast populations,
extensive lymphocytic infiltration, angiogenesis and, ultimately, outgrowth beyond the natural tissue borders into
cartilage and bone. In independent single-cell RNA-sequencing studies, we recently identified a novel
macrophage phenotype found enriched in the synovium of RA patients (Zhang et al. Nat Immunol. 2019;
Stephenson et al. Nat Comm. 2018). These macrophages express high levels of the EGF receptor (EGFR)
ligand HB-EGF and are hereafter referred to as ‘HBEGF+ macrophages’. Our preliminary data also demonstrated
that HBEGF+ macrophages are shaped by resident fibroblast factors along with pro-inflammatory cytokines
including TNF (Kuo et al. Sci Transl Med. 2019). This newly activated macrophage state then feedbacks to
activate fibroblast EGFR. Our central hypothesis posits that in RA synovial tissue, HBEGF+ macrophages are
polarized by fibroblasts and in turn stimulate fibroblast pathologic activity. A critical prediction is that inhibition of
mediators of this disease-associated crosstalk pathway will prevent tissue remodeling. We have developed an
experimental cell culture model system to study HBEGF+ macrophage differentiation and the pathologic impact
of their intercellular communication with synovial fibroblasts. We have also established a patient tissue ex vivo
drug response assay, which has proven effective in defining how medications function in the complex cellular
interactions of inflamed synovial tissue from clinically well-defined patients. Prior reports have established the
relevance of macrophage-fibroblast crosstalk as a powerful regulator of RA pathology, but these reports lacked
knowledge of the precise phenotypes of the synovial macrophages in RA (Rigor). With this new information and
all methods and materials in place, we can look to define which of the known pathologic tissue factors induce
this macrophage phenotype, specifically testing if IFNγ from abundant CD8+ T cells in the RA synovium, in
combination with TNF and PGE2, induces the HBEGF+ macrophage phenotype (Aim 1). Furthermore, it is
feasible to define how these macrophages drive RA synovial pathogenesis, in particular whether HB-EGF and/or
epiregulin (EREG), a second EGF ligand expressed by HBEGF+ macrophages, drive both a hypoxic response
and invasiveness in synovial fibroblasts and define which subtype of human synovial fibroblasts exhibit
invasiveness in response to these EGF ligands (Aim 2). Finally, we are able to test the impact of potential
inhibitors on HBEGF+ macrophage generation and pathologic function, focusing on the ADAM17/iRhom2
complex, which controls both the release of HB-EGF and TNF from macrophages (Aim 3). Completion of these
aims will leverage our finding of human disease-associated macrophages, define mechanisms of a new...

## Key facts

- **NIH application ID:** 10050193
- **Project number:** 1R01AI148435-01A1
- **Recipient organization:** HOSPITAL FOR SPECIAL SURGERY
- **Principal Investigator:** Laura T. Donlin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $445,000
- **Award type:** 1
- **Project period:** 2020-05-04 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10050193

## Citation

> US National Institutes of Health, RePORTER application 10050193, Macrophages in human autoimmune tissue pathology (1R01AI148435-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10050193. Licensed CC0.

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