Harnessing the immune response to improve functional healing

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Science Translational Medicine  17 Oct 2018:
Vol. 10, Issue 463, eaav3889
DOI: 10.1126/scitranslmed.aav3889


Interleukin-4–conjugated gold nanoparticles promote M2 macrophage polarization and functional muscle recovery in an ischemic mouse model.

A majority of tissue engineering approaches rely on stem cells and/or growth factors to promote tissue regeneration after injury. Here, the researchers attempt to control the immune response following injury as an alternative approach to improving tissue regeneration. Following injury, the immune system is responsible for maintaining a delicate balance between proinflammatory and pro-regenerative immune cells. M1 macrophages promote cell recruitment and proliferation, whereas M2 macrophages promote differentiation and tissue regeneration. The polarization switch from M1 to M2 macrophage phenotype is important for promoting functional tissue regeneration. Both cell phenotypes are critical; however, the presence of more M1 than M2 macrophages has been shown to inhibit tissue repair. To control this balance and promote functional tissue regeneration, Raimondo and Mooney used gold nanoparticles to deliver interleukin-4 (IL-4), a cytokine previously shown to promote M2 macrophage polarization.

Previous research has shown systemic delivery of IL-4 promotes M2 macrophage polarization. However, the requirement of high doses, due to a short half-life and lack of targeted delivery, limit the clinical use of IL-4 treatments. To address this issue, Raimondo and Mooney delivered IL-4 using gold nanoparticles, in which gold nanoparticles allowed longer IL-4 bioactivity and targeted delivering directly to the site of injury. To determine the impact of IL-4 on tissue regeneration, IL-4–conjugated gold nanoparticles were injected into mice with an ischemic muscle injury in their hindlimb. After injection, IL-4 was localized to the injected area and did not diffuse into the surrounding tissues. Mice that received the IL-4 nanoparticle injections showed increased muscle fiber area and improved muscle function compared with controls. Treatment with IL-4–conjugated gold nanoparticles resulted in a significant increase in M2 macrophages and corresponding decrease in M1 macrophages, highlighting the importance of promoting M2 macrophage polarization for functional tissue regeneration.

Although the current work was performed using a muscle injury model, controlling the inflammatory response is likely critical for other applications in tissue engineering. Moreover, the ability to control macrophage polarization could also have broad implications for the treatment of inflammatory diseases.

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