Myeloid lineage targeting to improve recovery from injury and surgery: Cellular and molecular mechanisms

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Project Summary Despite the number of people affected each year by persistent pain and poorly healed fractures after nonfatal traumatic and surgical injury it remains unclear what are the key components of the profound multicellular response to injury and how they can be manipulated to improve outcomes. In particular, peripheral injury mobilizes the immune system to resolve tissue damage, however, sustained immune activation can be detrimental and contribute to delayed healing. Myeloid-lineage cells are instrumental in the innate immune response to injury- peripherally, as macrophages, and centrally, as yolk sac-derived microglia. Nevertheless, the temporal and compartment-specific contributions of myeloid-lineage cells to bone healing, perioperative pain and surgical recovery have yet to be elucidated. Precise manipulation of these myeloid-lineage cells to establish causation is not possible in humans. To identify cellular and molecular targets for improving recovery we will therefore take advantage of a clinically informed mouse model of orthopaedic injury. Our central hypothesis is that there is a critical period during which myeloid-lineage cell involvement is crucial for proper recovery from injury; however, prolonged activation, marked by cytokine release and loss of homeostatic functions, can contribute to pain and impaired bone healing ultimately increasing the risk for long-term disability. To pursue this fundamental work, we will use a combination of molecular and whole organism approaches in which we have significant expertise including mouse models of complex orthopaedic trauma, affective-motivational readouts of persistent pain and functional impairment, specific transgenic manipulations and longitudinal imaging of bone and CNS tissues. In particular, this convergence of capabilities uniquely positions us to answer the following key knowledge gaps: 1) The innate immune response is instrumental to recovery, but can its dysfunction be monitored in vivo to identify at risk individuals? 2) What specific molecular signatures of activated myeloid- lineage cells can be targeted peripherally and centrally to improve outcomes? 3) Is the myeloid-lineage response to peripheral injury evolutionarily conserved and therefore translationally relevant? The proposed research builds on our previous work in a mouse model of chronic pain in which we showed that: 1) Myeloid-targeted positron emission tomography ligands can track dysfunctional innate immune activation, 2) Attenuation of macrophage and microglial activation can improve persistent pain, 3) New markers can be used to distinguish infiltrating macrophages from resident microglia in the spinal cord thus clarifying their unique contributions. Ultimately, these studies will establish how myeloid-lineage cells may be the initial cellular link between peripheral injury, poor bone healing and severe acute pain. Successful completion of the proposed studies will enhance our understanding of compartment-specific macrophage and microglia effects on healing after injury, identify cell- specific targets for intervention, and clarify when and in whom such treatments will provide the most benefit.