Low back pain (LBP) is the leading cause of disability globally and is most commonly associated with pathologies of the intervertebral disc (IVD), including spinal stenosis, disc herniation, and IVD degeneration. IVD cells within the local degenerative disc environment are known to produce abundant inflammatory cytokines and chemokines, leading to recruitment of immune cells, such as macrophages. The presence of both IVD cells and macrophages in the pro-inflammatory microenvironment further exacerbates the degenerative cascade, leading to production of additional inflammatory cytokines and catabolic enzymes that compromise the IVD ECM structural integrity. However, the individual contributions of IVD cells and macrophages on degeneration, as well as the impact of crosstalk between the cell types remains unknown. A systemic inflammatory response is also common in cases of chronic LBP, defined as lasting longer than 3 months. While systemic inflammation in the serum of patients with LBP has been widely observed in comparison to healthy controls, the impact of pain and disability severity on systemic inflammation has not been determined. Additionally, both the local and systemic inflammatory responses associated with IVD injury and LBP have been characterized independently; however, the connection between these responses and their role in the progression of pain has not been studied. This thesis addresses these questions through a variety of methodologies including characterization of clinical samples, in vivo injury modeling, and an in vitro co-culture system. First, transcriptomic analysis of whole blood from patients with chronic LBP and spine pathologies was performed to determine the signaling mechanisms contributing to pain and disability severity systemically. Circulating immune cell senescence, and decreased complement activation and Type I interferon signaling were shown to contribute to greater severity of disability in patients with LBP. Next, an inflammation-driven in vivo injury model utilizing intradiscal injection of the inflammatory stimulus, lipopolysaccharide (LPS), was developed to investigate the role of local inflammation in the progression of IVD degeneration. Intradiscal inflammatory stimulation increased degeneration, macrophage infiltration, and innervation, ultimately leading to a pain phenotype. RNA sequencing analysis of the AF and whole blood after injection was also performed to determine signaling mechanisms mediating the local and systemic inflammatory responses. Type I interferon signaling was commonly upregulated in both the AF and blood, indicating a direct connection between local and systemic inflammation. Additionally, an inverse relationship between the complement activation and neuronal signaling pathways provides an interesting parallel with the relationship observed between the complement system and disability severity clinically. An in vitro macrophage-IVD explant co-culture model was also created to gain understanding of the contributions of macrophages in the inflammatory microenvironment of the degenerating IVD. Using a transwell system limiting communication to paracrine signaling, pro-inflammatory M1 macrophages were shown to have detrimental effects increasing inflammation, while M2 macrophage were protective, decreasing production of inflammatory cytokines. Inflammatory-stimulated IVDs also polarized M0 macrophages towards an M1-like phenotype, further exacerbating inflammation and degradation. Taken together, this thesis indicates a key role for macrophages in the modulation of the local inflammatory environment. Local inflammation severity also directly regulates the systemic inflammatory response, contributing to a pain phenotype. Finally, in cases of chronic LBP clinically, systemic inflammation is dependent on pain and disability severity.