Numerous studies analyzed immune mediators in LDH and especially implicating macrophages in LDH regression (Table
1). Shamji et al. [
32] showed high expression levels of macrophage products like IL-4, IL-6, IL-12, and interferon gamma (IFN-γ) in herniated disc tissue. Other studies demonstrated that IVD tissue is also capable of spontaneously producing other molecules, such as the chemokines IL-8 and MCP-1, the main functions of which are chemotaxis of macrophages and angiogenesis [
37]. Furthermore, Kang et al. [
42] demonstrated that herniated discs release high levels of matrix metalloproteinases (MMPs), nitric oxide (NO), IL-6, and prostaglandin E2 (PGE2) and this production increases when the discs are stimulated with IL-1β, evidencing that IVD cells are biologically responsive to exogenous stimuli. Regarding IL-6, it has already been demonstrated in vitro that its production is induced when IVDs and macrophages are cocultured [
43]. More recently, Takada et al. [
44] showed that coculturing IVDs and macrophages upregulated IL-8, PGE2, and cyclooxygenase 2 (COX-2). In both studies, the mentioned biochemical mediators are mainly produced by macrophages. The latter study also showed that rat IVD autografts induced extensive macrophage infiltration in vivo, increasing the mRNA levels of TNF-α, IL-6, IL-8, and COX-2. TNF-α is required for IL-6 and PGE2 production, but not for IL-8 production, during IVD–macrophage interaction. Neutralization of TNF-α and IL-8 may be a valuable therapy for pain related with LDH [
44]. Other studies have also analyzed the interaction between macrophages and IVD tissue using cocultures between macrophages and chondrocytes or whole IVD. Haro et al. demonstrated that the production of both MMP-3 and MMP-7 was strongly upregulated in IVD cell/macrophage coculture, MMP-3 being produced by both chondrocytes and macrophages while MMP-7 is produced predominantly by macrophages. Moreover, the authors also revealed that disc-derived MMP-3 is required for the physical degradation of disc tissues and for macrophage infiltration, which ultimately leads to hernia resorption [
45]. In other studies, the same group demonstrated that MMP-7 released by macrophages contributes to the process of herniated disc resorption through the release of soluble TNF-α [
46,
47]. TNF-α is a potent inducer of many MMPs, such as MMP-3, and also of vascular endothelial growth factor (VEGF) that is implicated in the neovascularization of herniated discs [
47,
48]. The crucial role of MMP-7 in the initiation of herniated disc resorption resulted in the development of a recombinant human MMP-7 intradiscal therapy, which is in phase I/II clinical trials in the United States. This therapy avoids the side effects associated with surgery, such as nerve tissue damage [
49].
Table 1
Immune mediators implicating macrophages in LDH regression
IL-6, NO, PGE2, MMP-3, MMP-2/MMP-9 | Herniated IVD tissue | Human | |
IL-8, MCP-1 | Herniated IVD tissue | Human | |
IL-4, IL-6, IL-12, IFN-γ | Herniated IVD tissue | Human | |
MMP-3, MMP-7 | Coculture of IVD and macrophages | Mouse | |
MMP-7, TNF-α | Coculture of IVD and macrophages | Mouse | |
MMP-3, MMP-7, TNF-α, VEGF | Coculture of IVD and macrophages | Mouse | |
IL-6 | Coculture of IVD and macrophages | Rat | |
IL-8, PGE2, COX-2 | Coculture of IVD and macrophages | Rat | |