Interleukin-4 clicked surfaces drive M2 macrophage polarization

Driving macrophage (Mφ) polarization into the M2 phenotype provides exciting potential against various inflammatory diseases. Interleukin-4 (IL-4) leverages polarization into the M2-Mφ phenotype but its systemic use is constrained by dose-limiting toxicity. Consequently, we developed IL-4 decorated surfaces aiming for sustained and localized activity of the potent cytokine. IL-4 muteins were generated through genetic code expansion, replacing Lys 42 by unnatural amino acids (uAA). All muteins had wt-IL-4 comparable cellular performances and binding affinities to the IL4Rα. Copper catalyzed (CuAAC) and copper free strain promoted (SPAAC) [1+3]-dipolar azide alkyne cycloadditions were used to site-selectively anchor IL-4 at position 42 to agarose surfaces. The IL4-decorated surfaces provided sustained IL-4 activity as demonstrated by TF-1 cell proliferation and by M2 but not M1 polarization of M-CSF generated human Mφ. The approach demonstrated for IL-4 provides a blueprint for the engineering of cytokine-activated surfaces profiled for sustained and spatially controlled activity