ABSTRACT The most common forms of nervous system injury are traumatic lesions to peripheral nerves. Although axonal regeneration in the periphery is more robust than in the central nervous system, neuronal regeneration is often incomplete and associated with partial or complete loss of motor and sensory function, and the development of neuropathic pain. After injury, the distal portion of severed nerve fibers shed their myelin sheath and rapidly disintegrate, a process called Wallerian degeneration (WD). Blood-borne immune cells rapidly enter the injured nerve to aid repair Schwann cells (rSC) and nerve resident macrophages (Mφ) in the removal of degenerated myelin and axon remnants. Additionally, Mφ contribute to nerve debridement by phagocytosis of apoptotic cells (AC) that accumulate in the injured nerve, a process termed efferocytosis. Clearance of AC before they undergo lysis is critical to prevent secondary necrosis. Moreover, efferocytosis triggers Mφ reprogramming from a pro- to anti-inflammatory phenotype. This process has only recently been identified as a function of Mφ after sciatic nerve injury. The receptor mechanism of Mφ efferocytosis and its importance to nerve repair remain unknown. Single cell RNA-sequencing (scRNA-seq) of injured mouse sciatic nerve identified Mφ subpopulations expressing low-density lipoprotein receptor related protein 1 (Lrp1), a well characterized phagocytic receptor that has been linked to Mφ efferocytosis and reprogramming in non-neural models of inflammation and injury. The goal of this proposal is to understand whether efferocytosis is a unique function of specific Mφ subpopulations and how it contributes to overall nerve health after injury. The central hypothesis to be tested is that efferocytosis is a macrophage subpopulation specific function mediated by LRP1 to facilitate macrophage reprogramming, inflammation resolution, and axon regeneration. To test this hypothesis, two Specific Aims are proposed. Aim 1 will use a combination of FACS and scRNA-seq of phagocytic cells isolated from injured nerves of mouse lines expressing fluorescent reporters labeling either neutrophils or myelin to determine whether Mφ subpopulations exist that are specialized for efferocytosis or myelin phagocytosis, respectively. Aim 2 will assess the contribution of Lrp1 to Mφ function and nerve recovery using a genetic mouse model in which Lrp1 is conditionally ablated in monocytes and Mφ (Lrp1 cKO). Efferocytosis will be assessed by adoptively transferring neutrophils isolated from CD45.1;tdTomato “universal donor” mice into Lrp1 cKO mice on a CD45.2+ background. Inflammation and neural repair in the absence of Lrp1 in Mφ will be assessed using a combination of molecular, biochemical and behavioral assays. The proposed studies are expected to reveal a targetable mechanism in a specific Mφ population that impacts inflammation resolution, functional recovery, and pain development after acute nerve trauma. Understanding the c...