Treating Macrophages with Anti-inflammatory Nanoparticles as a Strategy to Improve Muscle Repair

Yan, Derek
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The macrophage is an immune cell that is involved in host defense. More recent research, however, has revealed that they also play a central role in mediating the skeletal muscle regenerative process. Upon muscle injury, macrophages are recruited to the damaged site and begin differentiating into a pro-inflammatory phenotype, known as the M1 phenotype. M1 macrophages secrete inflammatory cytokines to facilitate the acute response to muscle injury, and are characterized by phagocytosis of cellular debris and exhibiting strong microbicidal activity. However, another hallmark of inflammatory macrophages is the metabolism of arginine into nitric oxide (NO), which is further metabolized into other reactive oxygen species such as superoxide and peroxynitrite. If left unchecked, prolonged macrophage inflammation leads to muscle cell lysis due to the persistence of reactive oxygen radicals. The capacity of macrophages to stimulate myogenic cells to proliferate is also reduced if inflammation persists. To improve muscle regeneration, we have developed and synthesized a nanoparticle formulation that allows controlled reduction of macrophage inflammatory phenotype. Previous published studies have shown lactic acid and magnesium as chemical agents that attenuate M1 phenotype in macrophages. We developed a poly-lactic-co-glycolic acid (PLGA) nanoparticle emulsified with magnesium sulfate to attenuate the inflammatory phenotype in a murine macrophage cell line. This Magnesium-PLGA nanoparticle has been optimized to be uptaken by macrophages without affecting cell viability. We hope that these contributions make the first steps towards developing an injectable therapy to modulate macrophage phenotype, and can be used in conjunction with existing treatments to improve skeletal muscle repair following injury.