Itaconate promotes a wound resolving phenotype in pro-inflammatory macrophages

Area of Science:

• Immunology
• Metabolism
• Wound Healing

Background:

• Dysfunctional wound healing involves impaired extracellular matrix (ECM) remodeling, increased macrophages, and chronic inflammation.
• Macrophages are crucial for wound closure, secreting factors like transforming growth factor beta-1 (TGF-β).
• Macrophage metabolism influences their function, suggesting small molecules could treat wound-healing disorders.

Purpose of the Study:

• Investigate the effects of 4-octyl itaconate (4-OI) on macrophage ECM scavenging.
• Determine 4-OI's impact on macrophage inflammatory responses and wound healing-associated functions.

Main Methods:

• Used cultured human blood monocyte-derived macrophages (hMDM).
• Assessed the effects of 4-OI on lipopolysaccharide (LPS)-induced signaling pathways (p38 MAPK, NRF2).
• Measured inflammatory mediator production (TNF-α, COX-2), gene expression (TGFB1, MMP8), and cell surface marker levels (CD36).
• Developed an assay to quantify fibrous collagen uptake by macrophages.

Main Results:

• 4-OI reduced LPS-induced p38 MAPK signaling and production of TNF-α and COX-2.
• 4-OI increased TGFB1 gene expression and decreased MMP8 expression.
• Surface CD36 levels were elevated, while CD206 and CD11c remained unchanged.
• 4-OI reversed LPS-induced collagen uptake, linked to NRF2 signaling.

Conclusions:

• 4-octyl itaconate (4-OI) exhibits anti-inflammatory effects on macrophages.
• 4-OI may promote a wound-resolving macrophage phenotype by modulating metabolism and ECM interactions.
• This suggests 4-OI as a potential therapeutic agent for wound healing disorders.