Author ORCID Identifier
https://orcid.org/0009-0009-7002-6226
Date of Award
Winter 3-6-2025
Document Type
Thesis (Ph.D.)
Department or Program
Microbiology and Immunology
First Advisor
Patricia A. Pioli
Abstract
Systemic sclerosis (SSc) is a chronic autoimmune disease of unknown etiology. We have previously shown that macrophages (MØs) play a critical role in its pathogenesis; however, the mechanisms driving MØ activation in SSc remain poorly understood. This dissertation investigates the molecular signaling pathways and biochemical mechanisms underlying profibrotic MØ activity in SSc.
First, I identify a novel MØ-specific effect of mycophenolate mofetil (MMF), the standard-of-care treatment for SSc. While MMF is a well characterized lymphostatic, my findings demonstrate that its active metabolite, mycophenolic acid (MPA), is also capable of directly inhibiting myeloid viability and profibrotic MØ activation by suppressing de novo purine synthesis. These findings are novel, and suggest that the efficacy of MMF in SSc patients may result in part from its direct effect on myeloid cells.
Additionally, I characterize WNT5A as a key mediator of MØ-fibroblast crosstalk in SSc. Recombinant WNT5A induces profibrotic MØ activation through pSTAT3 signaling, while fibroblast-derived exosomal WNT5A modulates MØ oxidative metabolism via FZD5 signaling to promote profibrotic function. MØ-specific inhibition of oxidative metabolism or FZD5 was sufficient to block MØ-mediated activation of SSc fibroblasts in 2D culture models of SSc skin. These findings suggest that metabolic reprogramming is central to SSc MØ pathology.
Overall, this work highlights aberrant MØ metabolism as a driver of SSc pathogenesis and suggests that targeting MØ bioenergetics, including purine metabolism and noncanonical WNT-mediated metabolic signaling, may represent novel therapeutic avenues for SSc treatment.
Original Citation
Emily A Morris, Rezvan Parvizi, Nicole M Orzechowski, Michael L Whitfield, Patricia A Pioli, Mycophenolate mofetil directly modulates myeloid viability and pro-fibrotic activation of human macrophages, Rheumatology, 2024;, keae517, https://doi.org/10.1093/rheumatology/keae517
Recommended Citation
Morris, Emily Ann, "Mechanisms of Macrophage Metabolic Activation and Paracrine WNT Signaling in the Pathogenesis of Systemic Sclerosis" (2025). Dartmouth College Ph.D Dissertations. 359.
https://digitalcommons.dartmouth.edu/dissertations/359
