WFDC1 is a key modulator of inflammatory and wound repair responses

Area of Science:

• Immunology
• Molecular Biology
• Wound Healing Research

Background:

• WFDC1/ps20, a whey acidic protein, has known in vitro growth and immune functions, but its in vivo roles remain unclear.
• WFDC1 levels are observed to be lower in reactive stroma, hinting at a potential role in host responses.

Purpose of the Study:

• To investigate the in vivo functions of WFDC1/ps20 by generating and analyzing Wfdc1-null mice.
• To elucidate the mechanisms by which WFDC1 influences inflammatory and repair processes.

Main Methods:

• Generation of Wfdc1-null mice to assess developmental and adult phenotypes.
• Infection studies with influenza A virus to evaluate immune response.
• Wounding studies to assess skin repair rates.
• In vitro analysis of Wfdc1-null fibroblasts for adhesion and spheroid formation.
• Molecular analysis of osteopontin and MMP-9 expression and activity.

Main Results:

• Wfdc1-null mice showed normal development but altered inflammatory and repair processes.
• Influenza A infection led to significantly lower viral titers in Wfdc1-null mice, associated with increased macrophages and osteopontin.
• Wfdc1-null mice exhibited accelerated skin wound closure, linked to elevated osteopontin and macrophage recruitment.
• In vitro, Wfdc1-null fibroblasts displayed impaired spheroid formation and increased adhesion, reversed by osteopontin neutralization.
• Osteopontin and MMP-9 were upregulated in Wfdc1-null cells, suggesting a regulatory link.

Conclusions:

• WFDC1/ps20 plays a crucial role in modulating host defense and tissue repair mechanisms.
• The absence of WFDC1 leads to enhanced inflammatory and repair responses, partly through the regulation of osteopontin and MMP-9.
• Release from WFDC1 regulation, involving osteopontin processing by MMP-9 and subsequent macrophage recruitment, is a key component of these responses.