Pro-Inflammatory and Neurotrophic Factor Responses of Cells Derived from Degenerative Human Intervertebral Discs to the Opportunistic Pathogen Cutibacterium acnes

Abstract

Previously, we proposed the hypothesis that similarities in the inflammatory response observed in acne vulgaris and degenerative disc disease (DDD), especially the central role of interleukin (IL)-1β, may be further evidence of the role of the anaerobic bacterium Cutibacterium (previously Propionibacterium) acnes in the underlying aetiology of disc degeneration. To investigate this, we examined the upregulation of IL-1β, and other known IL-1β-induced inflammatory markers and neurotrophic factors, from nucleus-pulposus-derived disc cells infected in vitro with C. acnes for up to 48 h. Upon infection, significant upregulation of IL-1β, alongside IL-6, IL-8, chemokine (C-C motif) ligand 3 (CCL3), chemokine (C-C motif) ligand 4 (CCL4), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), was observed with cells isolated from the degenerative discs of eight patients versus non-infected controls. Expression levels did, however, depend on gene target, multiplicity and period of infection and, notably, donor response. Pre-treatment of cells with clindamycin prior to infection significantly reduced the production of pro-inflammatory mediators. This study confirms that C. acnes can stimulate the expression of IL-1β and other host molecules previously associated with pathological changes in disc tissue, including neo-innervation. While still controversial, the role of C. acnes in DDD remains biologically credible, and its ability to cause disease likely reflects a combination of factors, particularly individualised response to infection.

Evaluation of Antibacterial Drugs Using Silkworms Infected by Cutibacterium acnes

“…In a previous study using nucleus pulposus-derived disc cells in vitro, C. acnes cells (10 7 –10 8 cells/mL) were co-cultured with the disc cells and proinflammatory responses of the disc cells were induced by the addition of the C. acnes cells [ 34 ]. We injected C. acnes cells (3.3 × 10 8 cells/larva), and the range of viable cell number of C. acnes in silkworm hemolymph at 1 h after the injection was 3.2–4.8 × 10 7 cells/mL ( Figure 3 ).…”

Immuno-Modulatory Effects of Intervertebral Disc Cells

“…C. acnes , a Gram-positive anaerobic bacterium that is part of the natural skin microbiome, was the most abundant. Which is also associated with prosthetic joint infection ( Jauregui et al, 2021 ) and was shown to be able to interact with bone cells ( Aubin et al, 2017 ) and recently disc cells ( Capoor et al, 2021 ). Coagulase-negative (CoNS) bacteria of the genus Staphylococcus Rosenbach 1884 were the second most abundant ( Granville Smith et al, 2021 ).…”

“…However, most bacteria detected in the disc to date are Gram-positive and the potential influence of those bacteria on the disc remains poorly understood. Recently, Capoor et al (2021) stimulated human IVD cells with C. acnes demonstrating an induction of catabolic cytokine expression by native NP cells, suggesting that at least in some individuals the increased catabolic cytokines during disc degeneration could be triggered by bacterial infection. Further work is required to understand whether bacteria are present within the disc and whether bacteria could act as a trigger to the catabolic stimuli seen during disc degeneration, and whether the gut microbiome could influence disc degeneration ( Li W. et al, 2022 ).…”

Intervertebral disc cell chondroptosis elicits neutrophil response inStaphylococcus aureusspondylodiscitis

“…Chondroptosis was first described for articular chondrocytes in the growth plate of rabbit femurs (21,22) and considered to be an apoptotic-derived regulated cell death type, characterized by the activation of apoptotic caspases and formation of autophagic vacuoles to sequester and degrade cellular material (23). Furthermore, IVD cells have the ability to express and secrete a wide array of cytokines in response to various environmental stimuli (24–27). Cytokine secretion might be enhanced during chondroptosis of IVD cells and potentially cause a strong local immune stimulation (28,29).…”