Spinal cord injury (SCI) patients face devastating physical consequences associated with failed neural regeneration that severely impact their quality of life. One of these consequences include sustained inflammation at the SCI lesion site which further damages spared tissue, is aversive to cellular regeneration and prevents full functional recovery. Macrophages are one of the major classes of inflammatory immune cells that persists long-term at the lesion site and may represent a driving force behind the chronic inflammation observed after SCI. A subset of these cells with pro-inflammatory function are ?foamy? macrophages. These cells become lipid-laden due to excessive lipid uptake of myelin and cellular debris after injury and add to the harmful inflammatory milieu of the chronic SCI wound. CD36 is a receptor that drives lipid uptake in macrophages after SCI, and genetic deletion of this receptor has been shown to reduce lipid content and improve locomotor recovery. However, the effect of macrophage lipid loading on surrounding neural cells has not been specifically elucidated. Therefore, the first aim of this proposal will be to delineate the effect of foam cell-mediated inflammation on neuronal and oligodendrocyte survival and function in vitro. These outcomes will also be tested in vivo using a translationally relevant model of CD36 pharmacological inhibition. To understand the intrinsic processes driving this macrophage phenotype, the second aim of this proposal will address foam cell metabolism and its contribution to inflammation after SCI. Based on our preliminary data, we will test whether metabolic dysfunction in foam cells enhances secretion of inflammatory cytokines. These studies will evaluate my central hypothesis that excessive lipid uptake through receptors like CD36 produces harmful effects in the surrounding neural tissue that prevents functional recovery; lipid accumulation causes these effects through inducing metabolic dysregulation and driving foam cell inflammation. Together, this proposal will examine the role of macrophage lipid uptake and inflammation after SCI and the metabolic mechanisms by which foam cells contribute to cellular pathology after SCI, providing new mechanistic insight into potential therapeutic targets to enhance functional and cellular recovery after injury.
The spinal cord injury (SCI) site is characterized by chronic inflammation that is an impediment to tissue repair and functional recovery. Macrophages recruited from the periphery to phagocytose myelin and cellular debris become lipid-laden ?foamy? macrophages that exacerbate inflammatory activation at the lesion site. This proposal will address the mechanisms of foamy macrophage formation after SCI, and find novel therapeutic targets to improve lipid processing, restore metabolic function, and reduce inflammation in foam cells after SCI.
