Interleukin-8 as a therapeutic target for chronic low back pain: Upregulation in human cerebrospinal fluid and pre-clinical validation with chronic reparixin in the SPARC-null mouse model

Krock, Emerson; Millecamps, Magali; Anderson, Karen K.; Srivastava, Akanksha; Reihsen, Troy; Hari, Pawan; Sun, Yu; Jang, Seon Ho; Wilcox, George L.; Belani, Kumar G.; Beebe, David S.; Ouellet, Jean; Pinto, Manuel R.; Kehl, Lois J.; Haglund, Lisbet; Stone, Laura S.

doi:10.1016/j.ebiom.2019.04.032

Cited by 48 publications

(50 citation statements)

References 62 publications

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“…Moreover, we con rmed that protein expression of SASP factors (NGF, IL-1β, TNF-α and IL-8) was higher in the TLR-2 activated cells. These proteins were chosen since they have been associated to be IVD degeneration and TLR-2 induction and have been reported to be highly expressed in degenerate human and mice IVDs (35,37,38). Taken together our results validate that IVD cells from patients with back pain and IVD degeneration at both gene and protein level respond to TLR-2 activation.…”

Section: Discussionsupporting

confidence: 69%

O-vanillin Attenuated Toll-like Receptor 2 Induces Senescence in Intervertebral Disc Cells of Patients With Back Pain

Mannarino

Cherif

et al. 2020

Preprint

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Backgroud: There are an increased level of senescent cells and Toll Like Receptor-1 -2 -4 and -6 (TLR) expression in degenerating IVDs from back pain patients. However, it is currently not known if the higher expression is related to the senescent cells or if it is a more general increase on all cells. It is also not known if TLR activation in IVD cells will induce cell senescence.Methods: Cells from non-degenerate human IVD were obtained from spine donors and cells from degenerate IVDs came from patients undergoing surgery for low back pain. Gene expression of TLR-1,2,4,6, senescence and senescence-associated secretory phenotype (SASP) markers was evaluated by RT-qPCR in isolated cells. Matrix synthesis was verified with safranin-O staining and Dimethyl-Methylene Blue Assay (DMMB) confirmed proteoglycan content. Protein expression of p16INK4a, SASP factors and TLR-2 was evaluated by immunocytochemistry (ICC) and/or by enzyme-linked immunosorbent assay (ELISA). Results: An increase in senescent cells was found following 48h induction with a TLR-2/6 agonist in cells from both non-degenerate and degenerating human IVDs. Higher levels of SASP factors, TLR-2 gene expression and protein expression was found following 48h induction with TLR-2/6 agonist. Treatment with o-Vanillin reduced the number of senescent cells, and increased matrix synthesis in IVD cells from back pain patients. Treatment with o-Vanillin after induction with TLR-2/6 agonist reduced gene and protein expression of SASP factors and TLR-2. Co-localized staining of p16INK4a and TLR-2 demonstrated that senescent cells have a high TLR-2 expression.Conclusions: Taken together our data demonstrate that activation of TLR-2/6 induce senescence and increase TLR-2 and SASP expression in cells from non-degenerate IVDs of organ donors without degeneration and backpain and in cells from degenerating human IVD of patients with disc degeneration and backpain. The senescent cells showed high TLR-2 expression suggesting a link between TLR activation and cell senescence in human IVD cells. The reduction in senescence, SASP and TLR-2 expression suggest o-Vanillin as a potential disease modifying drug for patients with disc degeneration and backpain.

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Section: Discussionsupporting

confidence: 69%

O-vanillin Attenuated Toll-like Receptor 2 Induces Senescence in Intervertebral Disc Cells of Patients With Back Pain

Mannarino

Cherif

et al. 2020

Preprint

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“…Activation of neuronal TNF receptors increases the production of IL-1β, IL-6, and CCL2 [formerly known as monocyte chemoattractant protein-1 (MCP-1)]. Both IL-1β and IL-6 have been shown to have activity in acute inflammatory and chronic pain (146)(147)(148). Indeed IL-1β enhanced pain transduction and conduction via modulation of ion channels such as TRP ankyrin 1 (TRPA1), TRPV1, and Nav1.7.…”

Section: Peripheral Nociceptor Terminalmentioning

confidence: 99%

“…IL-8 has also been implicated in conditions such as chronic low back pain (LBP). Krock et al showed a specific upregulation of this chemokine in the cerebrospinal fluid of LBP patients with degenerating disks and a reduction of disk degeneration and chronic back pain in a mouse model (148). In a neuropathic orofacial pain condition, the burning mouth syndrome, patients present an elevated level of plasma IL-8, and this signature directly correlates with pain and depressive symptomatology (150).…”

Section: Peripheral Nociceptor Terminalmentioning

confidence: 99%

Neuraxial Cytokines in Pain States

et al. 2020

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A high-intensity potentially tissue-injuring stimulus generates a homotopic response to escape the stimulus and is associated with an affective phenotype considered to represent pain. In the face of tissue or nerve injury, the afferent encoding systems display robust changes in the input-output function, leading to an ongoing sensation reported as painful and sensitization of the nociceptors such that an enhanced pain state is reported for a given somatic or visceral stimulus. Our understanding of the mechanisms underlying this non-linear processing of nociceptive stimuli has led to our appreciation of the role played by the functional interactions of neural and immune signaling systems in pain phenotypes. In pathological states, neural systems interact with the immune system through the actions of a variety of soluble mediators, including cytokines. Cytokines are recognized as important mediators of inflammatory and neuropathic pain, supporting system sensitization and the development of a persistent pathologic pain. Cytokines can induce a facilitation of nociceptive processing at all levels of the neuraxis including supraspinal centers where nociceptive input evokes an affective component of the pain state. We review here several key proinflammatory and anti-inflammatory cytokines/chemokines and explore their underlying actions at four levels of neuronal organization: (1) peripheral nociceptor termini; (2) dorsal root ganglia; (3) spinal cord; and (4) supraspinal areas. Thus, current thinking suggests that cytokines by this action throughout the neuraxis play key roles in the induction of pain and the maintenance of the facilitated states of pain behavior generated by tissue injury/inflammation and nerve injury.

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“… 27 , 66 Knockout animals lacking IL-1β, IL-1 receptor 1, or MCP-1 demonstrate reduced or abrogated pain behavior in peripheral nerve injury models, and inhibition of IL-8 decreased pain in a rodent chronic low back pain model. 1 , 20 , 54 Attenuation of neuroinflammation, through inhibition of microglial activation, targeting of specific microglial genes, or selective depletion of spinal microglia, relatively consistently reverses pain hypersensitivity. 25 , 35 …”

Section: Introductionmentioning

confidence: 99%

Differential expression of cerebrospinal fluid neuroinflammatory mediators depending on osteoarthritis pain phenotype

Bjurström

Bodelsson

Montgomery

et al. 2020

Pain

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Neuroinflammation is implicated in the development and maintenance of persistent pain states, but there are limited data linking cerebrospinal fluid (CSF) inflammatory mediators with neurophysiological pain processes in humans. In a prospective observational study, CSF inflammatory mediators were compared between patients with osteoarthritis (OA) who were undergoing total hip arthroplasty due to disabling pain symptoms (n = 52) and pain-free comparison controls (n = 30). In OA patients only, detailed clinical examination and quantitative sensory testing were completed. Cerebrospinal fluid samples were analyzed for 10 proinflammatory mediators using Meso Scale Discovery platform. Compared to controls, OA patients had higher CSF levels of interleukin 8 (IL-8) (P = 0.002), intercellular adhesion molecule 1 (P = 0.007), and vascular cell adhesion molecule 1 (P = 0.006). Osteoarthritis patients with central sensitization possibly indicated by arm pressure pain detection threshold <250 kPa showed significantly higher CSF levels of Fms-related tyrosine kinase 1 (Flt-1) (P = 0.044) and interferon gamma-induced protein 10 (IP-10) (P = 0.024), as compared to subjects with PPDT above that threshold. In patients reporting pain numerical rating scale score ≥3/10 during peripheral venous cannulation, Flt-1 was elevated (P = 0.025), and in patients with punctate stimulus wind-up ratio ≥2, CSF monocyte chemoattractant protein 1 was higher (P = 0.011). Multiple logistic regression models showed that increased Flt-1 was associated with central sensitization, assessed by remote-site PPDT and peripheral venous cannulation pain, and monocyte chemoattractant protein-1 with temporal summation in the area of maximum pain. Multiple proinflammatory mediators measured in CSF are associated with persistent hip OA-related pain. Pain phenotype may be influenced by specific CSF neuroinflammatory profiles.

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Interleukin-8 as a therapeutic target for chronic low back pain: Upregulation in human cerebrospinal fluid and pre-clinical validation with chronic reparixin in the SPARC-null mouse model

Cited by 48 publications

References 62 publications

O-vanillin Attenuated Toll-like Receptor 2 Induces Senescence in Intervertebral Disc Cells of Patients With Back Pain

O-vanillin Attenuated Toll-like Receptor 2 Induces Senescence in Intervertebral Disc Cells of Patients With Back Pain

Neuraxial Cytokines in Pain States

Differential expression of cerebrospinal fluid neuroinflammatory mediators depending on osteoarthritis pain phenotype

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