The Role of TNFα and IL-1β in Intervertebral Disc Disease and Health
Abstract
Low back pain and associated intervertebral disc degeneration is a widespread, costly, and complex condition. Increased inflammatory cytokine expression, in particular tumor necrosis factor alpha (TNFα) and interleukin-1β (IL-1β) are thought to play a key role in disc disease. To investigate how global manipulation of these cytokines affects disc health we studied two hTNFα overexpression mouse models of different severity (Tg197 severe and TG less severe) and one IL-1α/β double knockout (IL-1KO) with the expectation that TNFα overexpression would accelerate disc disease and IL-1α/β knockout would be protective. Multiplex ELISA blood analysis revealed that TNFα overexpression increased the circulating levels of inflammatory cytokines while knocking out IL-1 reduced these concentrations. Bony changes, evaluated by micro-CT, mirrored the systemic inflammatory changes; TNFα overexpression lead to reduced bone volume while the IL-1KO animals had more vertebral bone mass. Despite changes, extensive histological characterization revealed that the discs of all three mouse models were largely unaffected. However, each model evidenced unique changes offering novel insights into the role of cytokines in disc health. At 16-weeks-old, some Tg197 mice had spontaneous annular tears, herniations, and immune cell infiltration suggesting that systemic inflammation predisposes discs to herniation. However, the intact levels appeared healthier, with more vacuolated cells. Due to the metabolically demanding disc niche it was not clear whether the NP compartment could support this increased cell load long-term or if given more time the incidence of herniation would increase, so the longer-living TG mice were studied at 9-months-old. The NP compartment of the TG mice retained the healthier more vacuolated cell morphology, a phenotypic change reflected DAVID analysis of microarray data. However, the AF of these mice suffered macrophage mediated destruction and cell death. IL-1KO mice should complementary changes in NP cell phenotype; IL-1KO NP cells were smaller than WT controls, suggesting a role for inflammation in maintaining vacuolated cells. Additionally, IL-1KO AF was more susceptible to age-mediated degeneration than the WT controls. Contrary to the established exclusively negative view of cytokines, this work suggests that TNFα and IL-1 play a positive role in maintaining disc health and matrix homeostasis.
Subject Area
Cellular biology
Recommended Citation
Gorth, Deborah J, "The Role of TNFα and IL-1β in Intervertebral Disc Disease and Health" (2021). ProQuest ETD Collection - Thomas Jefferson University. AAI28321986.
https://jdc.jefferson.edu/dissertations/AAI28321986
