Dysregulated S100A9 Expression Impairs Matrix Deposition in Chronic Wounds

Area of Science:

• Biomedical Science
• Wound Healing Research
• Molecular Biology

Background:

• Chronic non-healing wounds exhibit persistent inflammation and impaired extracellular matrix (ECM) synthesis.
• S100A8/A9 proteins are dysregulated in delayed wound healing, affecting immune cell function.

Purpose of the Study:

• To investigate the pathological role of S100A9 overexpression in fibroblast ECM function in impaired wound healing models.
• To explore S100A9 as a potential therapeutic target for chronic wound treatment.

Main Methods:

• Utilized db/db mice (diabetes model) and iron-overloaded mice (chronic venous leg ulcer model).
• Analyzed S100A8/A9 expression, ECM deposition, and inflammatory mediators in wound tissues.
• Investigated the mechanism of S100A9 action on fibroblast ECM functions via toll-like-receptor 4 (TLR4) signaling.
• Assessed the therapeutic effect of blocking S100A9 in db/db mouse wounds.

Main Results:

• Both mouse models showed delayed wound closure, sustained inflammation, and decreased ECM deposition, mirroring human chronic wounds.
• Prolonged S100A8 and S100A9 expression correlated with compromised ECM deposition in these models and in human chronic wounds.
• S100A9 was found to directly alter fibroblast ECM protein and enzyme expression via TLR4-dependent signaling.
• Blocking S100A9 in db/db mice restored fibroblast ECM functions and increased matrix deposition.

Conclusions:

• Dysregulated S100A9 directly contributes to compromised ECM deposition in chronic wounds.
• S100A9 plays an unrecognized pathological role in affecting fibroblast ECM functions.
• S100A9 represents a promising therapeutic target for enhancing tissue repair in chronic wounds.