Magnetic responsive hydroxyapatite scaffold modulated macrophage polarization through PPAR/JAK-STAT signaling and enhanced fatty acid metabolism

Despite the general observations of bone repair with magnetic cues, the mechanisms of magnetic cues in macrophage response during bone healing have not been systematically investigated. Herein, by introducing magnetic nanoparticles into hydroxyapatite scaffolds, an appropriate and timely transition from proinflammatory (M1) to anti-inflammatory (M2) macrophages during bone healing is achieved. The combined use of proteomics and genomics analysis reveals the underlying mechanism of magnetic cue-mediated macrophage polarization form the perspective of protein corona and intracellular signal transduction. Our results suggest that intrinsically-present magnetic cues in scaffold contribute to the upregulated peroxisome proliferator-activated receptor (PPAR) signals, and the activation of PPAR signal transduction in macrophages results in the downregulation of the Janus Kinase-Signal transducer and activator of transcription (JAK-STAT) signals and the enhancement of fatty acid metabolism, thus facilitating M2 polarization of macrophages. Magnetic cue-dependent changes in macrophage benefit from the upregulation of adsorbed proteins associated with "hormone" and "response to hormone", as well as the downregulation of adsorbed proteins related to "enzyme-linked receptor signaling" in the protein corona. In addition, magnetic scaffolds may also act cooperatively with the exterior magnetic field, showing further inhibition of M1-type polarization. This study demonstrates that magnetic cues play critical roles on M2 polarization, coupling protein corona, intracellular PPAR signals and metabolism.