Epidermal CFTR Suppresses MAPK/NF-κB to Promote Cutaneous Wound Healing

Area of Science:

• Dermatology and Cell Biology
• Molecular Mechanisms of Disease

Background:

• The role of Cystic Fibrosis Transmembrane conductance Regulator (CFTR) in skin wound healing is not fully elucidated.
• CFTR is known to influence signaling pathways like MAPK/NF-κB in other cell types.

Purpose of the Study:

• To investigate the role of CFTR in regulating MAPK/NF-κB signaling during cutaneous wound healing.
• To understand the mechanisms by which CFTR impacts keratinocyte behavior and inflammation in skin repair.

Main Methods:

• Utilized CFTR mutant (DF508) mice and a human keratinocyte cell line (HaCaT) with CFTR manipulation (knockdown/overexpression).
• Employed splint-excisional and incisional wound models, alongside a cell-scratch assay.
• Assessed epidermal inflammation, keratinocyte proliferation/differentiation, and MAPK/NF-κB signaling, using pathway inhibitors.

Main Results:

• CFTR deficiency (DF508 mice, HaCaT knockdown) led to delayed wound healing, increased inflammation, proliferation, and abnormal differentiation.
• CFTR knockdown in HaCaT cells induced phosphorylation of ERK, p38, and IκBα, indicating MAPK/NF-κB pathway activation.
• Restoration of normal healing, inflammation, proliferation, and differentiation was observed with CFTR overexpression or MAPK/NF-κB inhibition.

Conclusions:

• CFTR actively suppresses the MAPK/NF-κB pathway in keratinocytes.
• By inhibiting this pathway, CFTR mitigates inflammation, reduces excessive proliferation, and promotes proper keratinocyte differentiation.
• These actions collectively facilitate and enhance cutaneous wound healing.