Interleukin-4-Clicked Surfaces Drive M2 Macrophage Polarization

Area of Science:

• Biotechnology
• Immunology
• Materials Science

Background:

• Macrophage polarization into the M2 phenotype shows promise for treating inflammatory diseases.
• Interleukin-4 (IL-4) is a key cytokine for M2 polarization, but its systemic administration is limited by toxicity.
• Developing localized and sustained cytokine delivery systems is crucial for therapeutic applications.

Purpose of the Study:

• To engineer IL-4-decorated surfaces for sustained and localized M2 macrophage polarization.
• To overcome the dose-limiting toxicity associated with systemic IL-4 administration.
• To create a versatile platform for cytokine-activated surfaces with controlled activity.

Main Methods:

• Generated IL-4 muteins using genetic code expansion, replacing Lys42 with unnatural amino acids (uAAs).
• Site-selectively anchored IL-4 muteins to agarose surfaces using copper-catalyzed (CuAAC) and copper-free strain-promoted (SPAAC) cycloaddition reactions.
• Assessed IL-4 mutein activity, binding affinity to IL4Rα, and M2 polarization of human macrophages.

Main Results:

• IL-4 muteins retained cell-stimulation ability and IL4Rα binding affinity comparable to wild-type IL-4.
• The developed agarose surfaces demonstrated sustained IL-4 activity.
• These surfaces successfully induced M2, but not M1, polarization in M-CSF-generated human macrophages, confirmed by TF-1 cell proliferation.

Conclusions:

• Engineered IL-4 surfaces provide sustained and localized cytokine activity.
• This approach offers a viable strategy to mitigate systemic toxicity of IL-4 therapy.
• The cytokine-surface engineering platform can be adapted for various therapeutic applications requiring controlled cytokine delivery.