Prolonged Wnt3a exposure tolerizes macrophages to inflammatory stimuli

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Macrophages are key innate immune cells with diverse functions.
• The Wnt/β-catenin signaling pathway influences immune regulation, but its effect on macrophages is debated.
• Understanding Wnt signaling in macrophages is crucial for therapeutic strategies.

Purpose of the Study:

• To investigate the time-dependent effects of Wnt signaling on macrophage phenotype and function.
• To clarify the contradictory evidence regarding Wnt's impact on macrophages.

Main Methods:

• Murine bone marrow-derived macrophages were treated with Wnt3a, LPS/IFN-γ, or IL-4.
• Gene and protein expression were analyzed using bulk RNA sequencing, RT-qPCR, flow cytometry, and immunofluorescence.

Main Results:

• Acute Wnt3a stimulation upregulated inflammatory genes (Il6, Tnf, Il12b) in a time-dependent manner.
• Chronic Wnt3a exposure induced macrophage tolerance to inflammatory stimuli and upregulated anti-inflammatory markers (Il10).
• RNA sequencing revealed Wnt3a affects genes related to chemotaxis and cytokine activity.

Conclusions:

• Acute Wnt3a signaling promotes macrophage inflammatory activation.
• Chronic Wnt3a signaling induces a tolerant, anti-inflammatory macrophage phenotype.
• Macrophage plasticity and time-dependent responses are critical for understanding their immune roles.