NYMC Student Theses and Dissertations

Date of Award

5-18-2026

Document Type

Doctoral Dissertation - Open Access

Degree Name

Doctor of Philosophy

Department

Cell Biology

First Advisor

Mitchell S. Cairo, MD

Second Advisor

Yanling Liao, PhD

Abstract

Inflammation is a major driver in many aspects of recessive dystrophic epidermolysis bullosa (RDEB) pathology, including impaired wound healing, fibrosis, and potentially cutaneous squamous cell carcinoma development. Fibroblasts, as key stromal cells in the dermis, are responsible for orchestrating inflammatory responses through the secretion of cytokines and chemokines upon stimulation with IL-1α or IL-6. Suppressor of Cytokine Signaling 3 (SOCS3) functions as a negative feedback regulator of cytokine signaling and has emerged as a key modulator of inflammatory responses in immune cells and fibroblasts. Transforming Growth Factor Beta (TGFβ), a known driver of fibrosis in RDEB, has been implicated in altering the inflammatory phenotype of fibroblasts, but the mechanisms through which it intersects with SOCS3 mediated signaling regulation are unclear.

This dissertation explores the hypothesis that TGFβ suppresses SOCS3 expression in fibroblasts via DNA hypermethylation, altering their response to IL-1α and IL-6 stimulation. TGFβ conditioning for 72 hours significantly downregulated SOCS3 mRNA and protein levels, accompanied by increased DNA methylation at specific CpG rich sites in the SOCS3 promoter. Treatment with 5-azacytidine partially restored mRNA expression but did not recover protein levels, implicating additional post-translational mechanisms, beyond DNA hypermethylation, in the regulation of SOCS3.

SOCS3 knockdown via siRNA increased basal phosphorylated cJun, phosphorylated STAT3 levels, and inflammatory gene expression (IL6, CCL2, CXCL1, and CXCL2), yet blunted responses to cytokine stimulation. In contrast, TGFβ conditioned fibroblasts xiv displayed suppressed inflammatory signaling and gene expression with or without cytokine stimulation. Temporal profiling revealed rapid SOCS3 upregulation following cytokine exposure, even in the context of prior TGFβ induced suppression. Attenuations in phosphorylated cJun and phosphorylated STAT3 elevations following cytokine stimulation were more responsive to dynamic increases in SOCS3 rather than overall levels of expression.

Together, these findings support a nuanced model in which TGFβ suppresses SOCS3 to prime fibroblasts for greater attenuation of inflammatory signaling upon stimulation, rather than permitting unchecked activation. This dynamic regulation has potential implications for fibrotic diseases such as RDEB, where aberrant TGFβ signaling exists. Targeting the epigenetic and post-translational mechanisms underlying SOCS3 suppression may offer therapeutic opportunities to restore immune responsiveness in TGFβ mediated fibrotic or immune restrictive microenvironments.

Keywords

Inflammation, Fibroblasts, RDEB, IL-1α, TGFβ, SOCS3, CAF, cSCC

Disciplines

Cell Biology | Cellular and Molecular Physiology | Medicine and Health Sciences

Download

Share

COinS