NF-кB c-Rel modulates pre-fibrotic changes in human fibroblasts

Area of Science:

• Biochemistry
• Cell Biology
• Immunology

Background:

• Systemic sclerosis (SSc) is an autoimmune disease characterized by skin fibrosis, with limited treatment options.
• Fibrosis involves myofibroblast differentiation, excessive extracellular matrix (ECM) production, and increased cytoskeletal forces.
• Understanding fibroblast transformation is crucial for developing antifibrotic therapies targeting signaling pathways.

Purpose of the Study:

• To investigate the role of nuclear factor-kappa B (NF-κB) and its isoforms in the cellular mechanisms of fibrosis.
• To elucidate the specific NF-κB subunits involved in fibrotic processes in systemic sclerosis.

Main Methods:

• Utilized an in vitro model of skin fibrosis.
• Employing small interfering RNA (siRNA) to functionally abrogate the c-Rel subunit of NF-κB.
• Assessed dermal fibroblast contractility in 3D collagen matrices and measured directed migration and N-cadherin expression.

Main Results:

• Consistently observed induction of the c-Rel subunit of NF-κB in the fibrosis model.
• Functional abrogation of c-Rel diminished dermal fibroblast contractility in relaxed collagen matrices.
• c-Rel silencing reduced directed migration and decreased N-cadherin expression, indicating its role in cellular adhesion and migration.

Conclusions:

• The NF-κB subunit c-Rel is implicated in regulating key cellular processes in fibrosis.
• c-Rel influences fibroblast contractility, migration, and N-cadherin expression.
• Targeting NF-κB c-Rel may represent a novel therapeutic strategy to counteract fibrotic progression in SSc.