Enabled by drug delivery: Studying the role of brain-resident and infiltrating myeloid cell phenotype in brain damage associated with inflammatory disease

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Project Summary: Patients inflicted with a traumatic injury, autoimmune disease, viral infection, or prolonged exposure to toxins often experience acute brain damage, resulting in functional and anatomical changes within the brain. Scientists have uncovered two key mechanisms through which innate immune cells drive acute brain damage: infiltration of activated neutrophils and monocytes into the brain parenchyma from systemic circulation, and chronic activation of brain-resident microglia. However, there is a basic science ‘gap’ in our understanding of these overlapping inflammatory processes, which complicates the development of targeted therapeutics. To what extent are the brain resident microglia, as opposed to infiltrating blood-derived myeloid cells, responsible for acute brain injury in inflammatory disease? To address this overarching question, we invented two enabling drug delivery technologies. The first technology is a biocompatible and biodegradable nanogel, comprised of covalently crosslinked acrylic monomers, which delivers active protein specifically to macrophages. We will leverage this material to answer our first key question: To what extent is peripheral activation responsible for immune cell infiltration of the central nervous system (CNS) parenchyma? We hypothesize that monocyte and neutrophil activation within circulation will induce central infiltration in healthy mice, while exacerbating infiltration in inflammatory disease. We will optimize immunomodulatory variations of the nanogel to activate circulating innate immune cells toward inflammation (interferon gamma) versus tolerance (interleukin 10). We will evaluate the extent to which circulating innate immune cell activation using targeted nanogels influences the cells’ biodistribution within healthy mice and mouse models of inflammatory disease. The second technology is an injectable hydrogel encapsulating cytokines and donor macrophages that is suitable for intracerebral implantation. Through direct injection of immunomodulatory proteins and myeloid cells into the parenchyma of healthy mice, we will evaluate the impact of infiltrating myeloid cell phenotype on brain-resident microglia separate from any activation within or infiltration from the periphery. We will quantify the extent to which classically versus alternatively polarized macrophages, implanted within the brain parenchyma, activate brain- resident microglia toward inflammation and induce neurological deficit (i.e. functional, anatomical). As proof-of- concept, we will evaluate local delivery of anti-inflammatory cytokines and macrophages as a prophylactic treatment for inflammatory brain damage associated with an LPS challenge. The MIRA award will allow the PI (Clegg) to commit greater time and resources to these unanswered questions, interdisciplinary collaborations, training, and mentoring of a diverse scientific workforce. We anticipate that long-term investment in this line of inquiry will result in fundamental insights on the mechanism of inflammation-induced brain injury as well as translational technologies for specific disease indications.