Immuno-Modulatory Effects of Intervertebral Disc Cells

Abstract

Low back pain is a highly prevalent, chronic, and costly medical condition predominantly triggered by intervertebral disc degeneration (IDD). IDD is often caused by structural and biochemical changes in intervertebral discs (IVD) that prompt a pathologic shift from an anabolic to catabolic state, affecting extracellular matrix (ECM) production, enzyme generation, cytokine and chemokine production, neurotrophic and angiogenic factor production. The IVD is an immune-privileged organ. However, during degeneration immune cells and inflammatory factors can infiltrate through defects in the cartilage endplate and annulus fibrosus fissures, further accelerating the catabolic environment. Remarkably, though, catabolic ECM disruption also occurs in the absence of immune cell infiltration, largely due to native disc cell production of catabolic enzymes and cytokines. An unbalanced metabolism could be induced by many different factors, including a harsh microenvironment, biomechanical cues, genetics, and infection. The complex, multifactorial nature of IDD brings the challenge of identifying key factors which initiate the degenerative cascade, eventually leading to back pain. These factors are often investigated through methods including animal models, 3D cell culture, bioreactors, and computational models. However, the crosstalk between the IVD, immune system, and shifted metabolism is frequently misconstrued, often with the assumption that the presence of cytokines and chemokines is synonymous to inflammation or an immune response, which is not true for the intact disc. Therefore, this review will tackle immunomodulatory and IVD cell roles in IDD, clarifying the differences between cellular involvements and implications for therapeutic development and assessing models used to explore inflammatory or catabolic IVD environments.

Keywords: GWAS; agent-based model (ABM); artificial intelligence–AI; catabolism; immune-privileged microenvironment; inflammation; intervertebral disc degeneration; low back pain.

FIGURE 1

Comparison of a healthy and a degenerated IVD disc (focused on ECM components). In the intact IVD, the NP matrix mostly contains proteoglycans (PG) and non-oriented collagen type II fibers. The proteoglycans contain negatively charged sulfated groups leading to an intradiscal osmotic pressure crucial for the basal hydration of the NP and the biomechanical function of the IVD. Within the degenerated disc, the total content of PG decreases. Small non-aggregating PGs are present. This drop-in PG content negatively affects the swelling capacity of the disc. Additionally, during disc degeneration, the production of catabolic cytokines, matrix-degrading enzymes, and neurotrophic as well as angiogenic factors occur due to cellular changes. This can lead to blood and nerve vessel ingrowth in the AF. The AF is composed of highly oriented concentric lamella of type I collagen whereas the cell density is higher in intact than in degenerated discs.

FIGURE 2

Comparison of a healthy, degenerated, and herniated IVD discs (focused on cellular involvement). (A) Intact IVD: Native disc cells produce a plethora of cytokines and chemokines expressing the corresponding receptors and maintaining homeostasis in a para and autocrine manner. The CEP is intact with blood vessels. The NP has a high number of proteoglycans. AF cells aligned. (B) Degenerated IVD: Shift to catabolic environment. Cytokines are expressed by disc cells themselves. The CEP has a higher amount of blood vessels than in the intact IVD. Proteoglycan number decreases in the NP. In the AF, there is a loss of alignment and support for AF cells. (C) Herniated IVD with crack in CEP: As soon as the AF or CEP is ruptured during injury or disc degeneration, a route for migration of immune cells into the IVD is provided. Immune cells, including T cells, B cells, macrophages, neutrophils and mast cells, contribute to an inflamed environment within the disc, further increasing the cytokine and chemokine expression and leading to a viscous circle of inflammatory driven catabolism. A crack in CEP allows blood vessels to grow into the AF and NP. The AF herniates/bulges, which is where blood vessel in-growth primarily occurs.

FIGURE 3

Schematic diagram of the different factors contributing to the metabolic shift from anabolism to catabolism in IDD, including genetics and epigenetics, biomechanics, microenvironment, presence of bacteria and other factors. All these contributors can promote a downstream biochemical effects (matrix breakdown and neurotrophins production) leading to structural and biomechanical alterations, nerve ingrowth and blood vessel formation. Thus, involvement of immune system could be achieved by chemotaxis losing the immuno-privileged state of the IVD.

FIGURE 4

Flow chart of the intersection of experiments and computational modeling. (A) First, a literature review is necessary to determine the current state of the research. Then, the researcher can either perform additional experiments to fill gaps of knowledge in the literature, or use published data to create an in-silico model. (B) There are many options for experimental model design, including use of imaging modalities to view the state of the IVD, in-vivo animal studies which better examine the complexity of IDD, bioreactors and microfluidic devices that allow the investigation of mechanical loading or fluid flow in the IVD, and in-vitro/ex-vivo culture of the whole IVD or IVD cells from human or animal tissue. (C) In-silico models or methodologies can use published literature or additional experiments to provide deeper investigations into complex tissue (FEM), cell (ABM), protein (network modeling), and genetic responses (network modeling, GWAS) as well as explore interactions at multiple scales which would be difficult and expensive to do experimentally. These models can help identify novel parameters and interactions that should be validated or explored further through experiments.