Role of cytokines in intervertebral disc degeneration: pain and disc content

Abstract

Degeneration of the intervertebral discs (IVDs) is a major contributor to back, neck and radicular pain. IVD degeneration is characterized by increases in levels of the proinflammatory cytokines TNF, IL-1α, IL-1β, IL-6 and IL-17 secreted by the IVD cells; these cytokines promote extracellular matrix degradation, chemokine production and changes in IVD cell phenotype. The resulting imbalance in catabolic and anabolic responses leads to the degeneration of IVD tissues, as well as disc herniation and radicular pain. The release of chemokines from degenerating discs promotes the infiltration and activation of immune cells, further amplifying the inflammatory cascade. Leukocyte migration into the IVD is accompanied by the appearance of microvasculature tissue and nerve fibres. Furthermore, neurogenic factors, generated by both disc and immune cells, induce expression of pain-associated cation channels in the dorsal root ganglion. Depolarization of these ion channels is likely to promote discogenic and radicular pain, and reinforce the cytokine-mediated degenerative cascade. Taken together, an enhanced understanding of the contribution of cytokines and immune cells to these catabolic, angiogenic and nociceptive processes could provide new targets for the treatment of symptomatic disc disease. In this Review, the role of key inflammatory cytokines during each of the individual phases of degenerative disc disease, as well as the outcomes of major clinical studies aimed at blocking cytokine function, are discussed.

Figures

Figure 1

Relationship between key vertebral structures, a herniated cervical intervertebral disc and spinal nerves A) Schematic shows extrusion of the nucleus pulposus through annular fissures of a degenerating intervertebral disc. The herniated tissue impinges on a spinal nerve close to the dorsal root ganglion, causing an inflammatory response resulting in radicular pain. B) T2 MRI image showing a lumbar disc herniation at L5-S1 in patient with symptomatic disc disease (arrow).

Figure 1

Relationship between key vertebral structures, a herniated cervical intervertebral disc and spinal nerves A) Schematic shows extrusion of the nucleus pulposus through annular fissures of a degenerating intervertebral disc. The herniated tissue impinges on a spinal nerve close to the dorsal root ganglion, causing an inflammatory response resulting in radicular pain. B) T2 MRI image showing a lumbar disc herniation at L5-S1 in patient with symptomatic disc disease (arrow).

Figure 2

IL-1α and IL-1β synthesis and signal transduction pathway. IL-1α and -β are synthesized as precursor proteins (pro-IL-1, pro-IL-1β) which then undergo proteolytic cleavage by either calpain or caspase-1 to produce the mature active forms, mIL-1α and mIL-β respectively. While pro-IL-1β is biologically inactive, myristoylated membrane associated pro-IL-1α can signal through the IL-1R to initiate cell-to-cell signaling. In addition, nuclear translocation of pro-IL-1α or the cleaved N-terminal pro-peptide that retains its nuclear localization sequence (NLS), elicits biological functions. Pro-IL-1α, mIL-1α and mIL-β all bind to IL-1RI, which recruits the IL-1 receptor accessory protein (IL-1RAcP) as a co-receptor. The receptor complex recruits two adaptor proteins, the myeloid differentiation primary response gene 88 (MYD88) and interleukin-1 receptor-activated protein kinase (IRAK). Sequential phosphorylation of IRAK4, IRAK1, IRAK2 and lastly TRAF6, an E3 ubiquitin ligase, results in polyubiquitination of signaling molecules, such as TGF-β-activated protein kinase (TAK-1) at K63. This modification allows for the association of TAK-1 with TRAF6 and subsequent activation of many signaling proteins: JNK, p38 and ERK1/2 as well as transcription factors: NF-κB and AP-1 which control expression of a number of inflammatory and catabolic genes. Signaling through IL-1 receptor complex is modulated by inhibitory actions of IL-1RII, sIL-1RII, sIL-1RAcP as well as IL-1 family member, IL-1 receptor antagonist (IL-1Ra).

Figure 3

Role of different classes of immune cells in amplifying the inflammatory response during intervertebral disc degeneration and the generation of back and radicular pain. Proinflammatory cytokines and soluble factors are secreted by both the NP and AF cells of the disc as well as immunocytes. Subtype of CD4+ TH cells (except TREG), CD8+ Tc, neutrophils, macrophages, B cells and mast cells infiltrate degenerate as well as herniated disc tissues. Major types of molecules that are secreted by the immune cells and their contribution to the disease process is listed. These proinflammatory factors promote expression of catabolic genes while at the same time suppressing expression of critical matrix genes by the NP and AF cells. The imbalance between synthesis and catabolism further accelerates degeneration, compromises tissue integrity and promotes pain generation.

Figure 4

Schematic of major interdependent phases leading to disc degeneration and pain. Following initial insult/s, disc cells upregulate expression of inflammatory cytokines and chemokines that include TNF-α, IL-β, IL-6 as well as IL-17 and CCLs. In this inflammatory environment, disc cells express several catabolic molecules like SDC4, ADAMTS-4/5, MMPs. These enzymes promote degradation of predominant extracellular matrix molecules such as aggrecan (ACAN) and collagen II (Col2). Continuous structural breakdown of matrix molecules of the NP and AF results in mechanical instability, annular tears and in many instances herniation. In the second phase of the disease, release of chemokines and cytokines from the degenerated disc enhances activation and infiltration of immunocytes into tissues further amplifying the inflammatory response. Infiltration of immune cells is accompanied by the appearance of microvasculature and nociceptive nerve fibers that arise from the dorsal root ganglion (DRG). In the third phase of the disease, neurogenic factors in particular NGF and BDNF produced by the herniated disc as well as the immunocytes induce expression of the pain associated cation channels like ASIC3 and Trpv1 in the DRGs. In this inflammatory milieu, activation of these channels is likely to promote discogenic pain and reinforce cytokine mediated disc degeneration. Possible sites of pharmacological intervention are indicated.