# Exosome-mediated Cooperative Mechanisms of Macrophage/Fibroblast Activation in Systemic Sclerosis

> **NIH NIH R21** · DARTMOUTH COLLEGE · 2022 · $260,431

## Abstract

ABSTRACT
Systemic sclerosis (SSc) is a chronic autoimmune disease of unknown etiology that is characterized by
vasculopathy, fibrosis, and inflammation. There is no cure for SSc and there are very few FDA-approved disease-
modifying treatments. While the contribution of fibroblasts to disease development is widely appreciated, recent
studies suggest macrophages (MØs) also play a role in the pathogenesis of SSc. In recently published work,
we developed an immunophenotypic profile for SSc MØs, and demonstrated that co-culture of MØs with SSc
dermal fibroblasts resulted in mutual activation of these cell types. However, the factors responsible for SSc MØ
activation are unknown. In this regard, our new preliminary studies implicate SSc dermal fibroblast-derived
exosomes as mediators of MØ activation in SSc. We show that uptake of SSc dermal fibroblast-derived
exosomes induces profibrotic MØ activation. In addition, SSc fibroblast-activated MØs stimulate SSc fibroblast
production of inflammatory cytokines and extracellular matrix (ECM) components. Therefore, we hypothesize
that exosome-stimulated MØs and SSc fibroblasts engage in reciprocal activation. The goal of this study
is to determine the mechanisms through which secreted fibroblast-derived exosomes and MØs promote fibrotic
and inflammatory activation in SSc. We will define the molecular mechanisms, pathways, and key molecules
that mediate cross-talk between fibroblast exosomes and MØs in SSc, and will test the therapeutic efficacy of
targeting these regulators using a recently developed 3D human SSc skin model. Results of this work will provide
the rational basis for the development of novel and effective treatments for SSc. The aims that will be tested in
this application are:
1. Define fibroblast exosomal cargo and identify the components that regulate MØ activation in SSc.
 Genomic and molecular biology approaches will be used to identify the exosome mediators that induce
 SSc MØ activation and to identify the signaling pathways that underlie this activation.
2. Determine how exosomal-mediated changes in MØ activation promote inflammation and fibrosis in SSc.
Co-culture studies demonstrate that SSc MØs induce activation of SSc fibroblasts, implicating a role for
MØ-derived factors in the induction and maintenance of fibrosis. This aim will determine how SSc MØ
activation impacts fibroblast activation.

## Key facts

- **NIH application ID:** 10441758
- **Project number:** 1R21AI169420-01
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Patricia A. Pioli
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $260,431
- **Award type:** 1
- **Project period:** 2022-04-25 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10441758

## Citation

> US National Institutes of Health, RePORTER application 10441758, Exosome-mediated Cooperative Mechanisms of Macrophage/Fibroblast Activation in Systemic Sclerosis (1R21AI169420-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10441758. Licensed CC0.

---

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