IL-6 trans-signaling in a humanized mouse model of scleroderma

Area of Science:

• Immunology
• Fibrosis Research
• Humanized Mouse Models

Background:

• Fibrosis pathogenesis involves complex immune and mesenchymal cell interactions.
• Understanding human fibrosis requires fully humanized model systems, which are currently lacking.
• MISTRG6 mice offer a novel platform for studying human immune responses in disease.

Purpose of the Study:

• To develop and utilize a humanized MISTRG6 mouse model to investigate scleroderma fibrosis.
• To identify cellular and molecular mechanisms driving human fibrosis in vivo.
• To assess the therapeutic potential of healthy immune cells in mitigating fibrosis.

Main Methods:

• Engineered MISTRG6 mice with human gene replacements for immune system development.
• Engrafted MISTRG6 mice with human hematopoietic stem cells (HSCs) and scleroderma/healthy skin grafts.
• Analyzed cellular composition, gene expression (collagen, interferon), and T cell activation markers in skin grafts.
• Investigated the role of IL-6 trans-signaling in fibrosis development and resolution.

Main Results:

• Scleroderma skin grafts in humanized mice showed human immune cells, endothelial cells, pericytes, and mouse fibroblasts.
• HSC engraftment significantly reduced fibrosis markers, including collagen and interferon gene expression.
• Fibrosis improvement correlated with decreased T cell activation and reduced human IL-6 expression by mesenchymal cells.
• Identified IL-6 trans-signaling, driven by CD4 T cells and fibroblasts, as a key mechanism in fibrosis.

Conclusions:

• MISTRG6 mice successfully modeled human scleroderma fibrosis, demonstrating IL-6 trans-signaling as a critical driver.
• Healthy bone marrow-derived immune cells mitigated fibrosis, suggesting potential for immune-based therapies.
• This model provides new insights into fibrosis regulation and therapeutic strategies for scleroderma.