NYMC Student Theses and Dissertations

Date of Award

3-16-2026

Document Type

Doctoral Dissertation - Open Access

Degree Name

Doctor of Philosophy

Department

Microbiology and Immunology

First Advisor

Raj K. Tiwari

Second Advisor

Chandra Shekhar Bakshi

Third Advisor

Jan Geliebter

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a devastating inherited blistering disorder caused by biallelic mutations in COL7A1, resulting in deficiency of type VII collagen (C7) and loss of dermal–epidermal adhesion. Beyond mechanical fragility, RDEB is characterized by chronic inflammation, progressive fibrosis, impaired wound healing, severe pain, and an exceptionally high risk of aggressive cutaneous squamous cell carcinoma. Emerging transcriptomic and cytokine profiling studies have identified interleukin-1 alpha (IL-1α) as a dominant and temporally upstream inflammatory mediator in RDEB skin. The central hypothesis of this dissertation is that IL-1α signaling functions as a key initiator and amplifier of inflammation-driven pathology in RDEB, and that genetic or pharmacologic inhibition of IL-1 signaling will attenuate inflammation, improve wound healing, reduce fibrosis, and ameliorate pain in RDEB mouse models. To test this hypothesis, both genetic and pharmacologic approaches were employed. A hypomorphic COL7A1 mouse model (C7hypo), which recapitulates chronic RDEB manifestations, was crossed with IL-1 receptor type 1 knockout (IL-1R1KO) mice to generate C7hypoIL-1R1KO animals. These mice were evaluated for survival, disease progression, inflammatory cell infiltration, and alterations in molecular signaling. In parallel, pharmacologic IL-1 inhibition was performed using anakinra (IL-1R1 antagonist) and bermekimab (IL-1α–neutralizing antibody). Functional assays included excisional wound healing models, survival analysis, von Frey mechanical pain testing, quantitative real-time PCR, ELISA-based cytokine profiling, immunofluorescence, and gelatin zymography to assess matrix metalloproteinase (MMP) activity. In vitro studies were conducted to interrogate IL-1α–driven transcriptional responses and matrix remodeling pathways. Genetic deletion of IL-1R1 significantly improved survival, delayed the onset of digit deformities, and reduced cutaneous immune cell infiltration in C7hypo mice. C7hypoIL-1R1KO mice attenuated nuclear factor kappa B (NF-κB) signaling and decreased circulating neutrophil and monocyte counts, supporting a central role for IL-1α in sustaining systemic inflammation. Pharmacologic IL-1α inhibition prolonged survival in a dose-dependent manner and significantly accelerated wound closure. Both genetic and pharmacologic IL-1 blockade increased pain tolerance following wounding, suggesting a direct role for IL-1 in inflammatory nociceptive sensitization. Molecular analyses demonstrated that IL-1 inhibition reduced pro-inflammatory gene expression and promoted a pro-resolution transcriptional profile. Notably, IL-1α selectively induced MMP-3 in fibroblasts, implicating an IL-1–MMP–TGF-β axis as a potential mechanistic bridge between inflammation and fibrosis. Collectively, these findings establish IL-1α signaling as a critical upstream driver of inflammation, impaired wound healing, pain sensitization, and matrix remodeling in RDEB. Targeting IL-1, particularly IL-1α, represents a rational therapeutic strategy capable of modifying both inflammatory and fibrotic components of disease. These results provide mechanistic insight into RDEB pathogenesis and support further translational investigation of IL-1α–directed therapies as systemic disease-modifying interventions.

Disciplines

Immunology and Infectious Disease | Laboratory and Basic Science Research | Medicine and Health Sciences | Microbiology

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