Project Summary Intervertebral disc herniation is a major cause of back/leg pain, which affects 80% of people with an estimated annual cost of $100 billion in the U.S. alone. Treatment options for disc herniation and its associated pain are very limited, largely due to insufficient understanding of pathological processes. Current research indicates that inflammation is a key contributor to back/leg pain after disc herniation in both acute and chronic phases. Others and we have found that macrophages are the predominant infiltrated cells at disc hernia sites. Macrophages may play distinct roles in various phases of disc herniation with tissue- and disease stage-specific phenotypes due to their remarkable plasticity and sensitivity in response to microenvironment cues. Our preliminary data revealed a mixed population of macrophages infiltrated at disc hernia sites and transiently depletion of macrophages reduced local inflammation. However, our knowledge of dynamic phenotypes and functions of infiltrated macrophages in disc herniation remains scarce. Our central hypothesis is that specific subpopulations of macrophages contribute to the progression of disc herniation at different stages and that modulation of macrophages will alleviate inflammation-induced pain and restore disc homeostasis. Our objective of this R01 is to better characterizing macrophage phenotypes, functions, and macrophage-disc crosstalk in disc herniation and pain at a mechanistic level, which facilitates our long-term goal to develop disease-modifying therapies for disc herniation and associated back/leg pain. Successful completion of this project will significantly advance our understanding of macrophage functions in disc herniation and lay a solid foundation for future therapeutic development, such as a selectively macrophage-targeted immunomodulation strategy.