Developing macrophage-based therapies for peripheral nerve injuries

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Summary Peripheral nerve injuries, whether the result of trauma, surgical complications, or neuropathies, afflict millions of people in the United States alone and are a major cause of disability and suffering throughout the world. The symptoms of peripheral nerve injury include numbness, tingling, muscle weakness, pain, and gait dysfunction. Despite the critical need, there are currently no approved therapies to accelerate peripheral nerve regeneration following injury. Though many researchers are focusing their investigations of nerve injury on components of the peripheral nerve itself, particularly neurons and Schwann cells, we have taken a novel approach and are focusing on components of the immune system-- specifically macrophages. Immunotherapy, or the manipulation of the immune system to treat human diseases, is a rapidly growing area in medicine that has shown great promise, particularly in treating autoimmune diseases and cancer. Immunotherapies can take many forms, including monoclonal antibodies, checkpoint inhibitors, and regulatory T lymphocyte transfusions. Though not currently used for treating human diseases, macrophages could also be harnessed to treat select diseases, with peripheral nerve injuries being a potential target due to disruption of the blood-nerve barrier and the established role of macrophages in peripheral nerve regeneration. Building on research demonstrating the importance of metabolism for the function of macrophages, we are studying the impact of alterations in a critical metabolic transporter, monocarboxylate transporter 1 (MCT1), on the function of macrophages. We recently published a paper showing that downregulation of MCT1 selectively in macrophages impairs phagocytosis, reduces production of pro-regenerative cytokines, and impairs recovery from peripheral nerve injury. More importantly from a clinical perspective, we also found that upregulation of MCT1 selectively in macrophages accelerates peripheral nerve regeneration and that macrophages injected intravenously into mice target the injured nerve and participate in repair. Based on these results, our current proposal will investigate two potential mechanisms for accelerating nerve recovery from injury in mice. In Aim 1, we will transform macrophages ex vivo to upregulate MCT1 or pro-regenerative pathways with lipid nanoparticles expressing MCT1 plasmid or encapsulating baicalin, respectively, and test whether adoptive cell transfer of these transformed macrophages accelerates nerve repair and recovery. In Aim 2, we will test whether these same lipid nanoparticles are capable of transforming macrophages in vivo following direct intravenous injections, resulting in accelerated recovery from peripheral nerve injuries. If successful, the experiments in this proposal will not only validate a novel technique and target for accelerating nerve recovery following injury, but also potentially provide an agent for manipulating macrophages in other macrophage-dependent conditions, such as non-healing skin wounds, pulmonary or liver fibrosis, and muscle injuries.