Editors' ChoiceCARDIAC REPAIR

GO minions—Polarize and repair!

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Science Translational Medicine  28 Feb 2018:
Vol. 10, Issue 430, eaas8967
DOI: 10.1126/scitranslmed.aas8967

Abstract

Graphene oxide may be able to play an important therapeutic role after cardiac injury by modulating immune cell phenotype and changing macrophage polarization.

Immune cells are a lot like minions—they tend to crowd around when something bad happens. While carrying out their specific roles following an injury, immune cells, also like minions, sometimes make things worse. For example, after a heart attack, there is an increase in reactive oxygen species (ROS) and initiation of an inflammatory cascade that often results in heart failure. Macrophages are polarized in this cascade of events—existing in an inflammation-propagating “M1” phenotype or an inflammation-resolving “M2” phenotype. Both phenotypes are required for successful tissue repair, but in many cases M1 cells persist too long—the lovable minion that gets out of hand, creating an inflammatory state that overwhelms his reparative M2 co-workers. Therefore, one might ask: can you change the polarization of your macrophage minions in a timely manner to maximize cardiac repair?

Han et al. say yes and have put forward an exciting new technology to do just that. Prior to this work, immune modulation has often been achieved through cell-based therapies in the preclinical setting and in early stage clinical trials. However, these therapeutic systems are limited by several technical and financial challenges. Therefore, the authors investigated the use of graphene oxide (GO), which is an antioxidant that can also efficiently transfect genes. GO was administered at a certain time to both attenuate inflammation and deliver a gene to change macrophage polarization from M1 to M2, thereby enhancing endogenous repair after myocardial infarction (MI) in mice. Functionalized GO (called MGC particles) showed no cytotoxicity to macrophages, demonstrated selective uptake into M1 macrophage cells, and had no uptake in other cells present in cardiac tissue after injury. The authors show in vivo that cellular apoptosis of cardiomyocytes was reduced four days after injury following treatment with interleukin-4 (IL-4) plasmid DNA MGC particles, but the number of macrophages infiltrating into the infarcted area was surprisingly unchanged. Instead, the authors show a decrease in M1 markers (e.g., IL-6, neuronal nitric oxide synthase, tumor necrosis factor–α) and increase in M2 markers (e.g., IL-10, CD206, Cx43), suggesting a shift in phenotype from M1 to M2 macrophages, which then drives cardiac repair. Indeed, when the authors assessed remodeling in the injured region of the heart of the IL-4 and MGC-treated group, they noted higher blood vessel density, less fibrosis, and decreased inflammation—all leading to greater recovery of cardiac function and improved survival.

The authors show a promising technology that could modulate immune cell phenotypes by changing macrophage polarization after injury. Although the technology is still in development, the next steps include evaluation of the long-term effect of GO on the immune system, off-site toxicity effects of immune modulation, and effect of GO on superoxide and other radicals. Given the critical role that ROS and inflammation play in mediating many diseases, harnessing the state of immune cells could be a powerful technology—much like directing minions to achieve world domination!

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