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

Stanford University, Stanford CA

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Abstract

Project Summary Despite the number of people affected each year by persistent pain after trauma or surgery the key components of the profound multicellular response to injury and how they can be manipulated to improve outcomes remains unclear. Peripheral injury mobilizes the immune system to resolve tissue damage, however, sustained immune activation can delay 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 time and compartment-specific contributions of myeloid cells to perioperative pain and successful recovery have yet to be elucidated. How to regulate this delicate balance, between pro-resolution and pro-inflammatory contributions of myeloid cells is a crucial topic our lab has been interested in for many years. During the initial grant cycle we have made several key discoveries in this area: 1) Different mouse models of peripheral injury exhibit distinct spatial and temporal accumulation of macrophages at the site of injury providing a potential biomarker for diagnosis and myeloid-targeted therapy monitoring, 2) Microglia exist in a range of heterogeneous states, including a “pro-resolution” state which contributes to recovery after injury and exhibits a unique transcriptome, 3) The intersection of mouse microglial sequencing data with a newly generated human spinal cord single microglial nuclei dataset using advanced bioinformatic analyses provides genes of interest for further study. These findings, and the technical capabilities we have developed during the prior cycle, uniquely position us to address the following key knowledge gaps over the next 5 years: 1) The myeloid immune response can be pro- inflammatory or pro-resolution, can these states be monitored in vivo to understand poor or successful recovery? 2) What specific molecular signatures of pro-resolution microglia can be targeted to improve outcomes? 3) Can we leverage microglial heterogeneity in humans to discover better translational targets? Precise manipulation of myeloid-lineage cells to establish causation is not possible in humans, however, the overall vision for the research program is to perform “clinically-informed basic science” by observing variables most significant to human recovery and testing them systematically in pre-clinical models. This will include consideration for sex and age as biological variables, the latter being particularly important as age is a major risk factor for injury and poor recovery. Our approach integrates concepts of injury mechanism (using varied mouse models), cell location (evaluating both peripheral and central involvement) and cellular heterogeneity (recognizing that myeloid cells exist in a range of states). Successful completion of the proposed studies will enhance our understanding of compartment-specific myeloid cell effects on healing after injury, identify cell- specific targets for intervention, and clarify when and in whom such treatments will provide the most benefit.