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

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

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Background: Low back pain (LBP) is the leading global cause of disability and is associated with intervertebral disc degeneration (DD) in some individuals. However, many adults have DD without LBP. Understanding why DD is painful in some and not others may unmask novel therapies for chronic LBP. The objectives of this study were to a) identify factors in human cerebrospinal fluid (CSF) associated with chronic LBP and b) examine their therapeutic utility in a proof-of-concept pre-clinical study. Methods: Pain-free human subjects without DD, pain-free human subjects with DD, and patients with chronic LBP linked to DD were recruited and lumbar MRIs, pain and disability levels were obtained. CSF was collected and analyzed by multiplex cytokine assay. Interleukin-8 (IL-8) expression was confirmed by ELISA in CSF and in intervertebral discs. The SPARC-null mouse model of progressive, age-dependent DD and chronic LBP was used for pre-clinical validation. Male SPARC-null and control mice received systemic Reparixin, a CXCR1/2 (receptors for IL-8 and murine analogues) inhibitor, for 8 weeks. Behavioral signs of axial discomfort and radiating pain were assessed. Following completion of the study, discs were excised and cultured, and conditioned media was evaluated with a protein array. Findings: IL-8 was elevated in CSF of chronic LBP patients with DD compared to pain-free subjects with or without DD. Chronic inhibition with reparixin alleviated low back pain behaviors and attenuated disc inflammation in SPARC-null mice. Interpretation: These studies suggest that the IL-8 signaling pathway is a viable therapy for chronic LBP. Fund: Supported by NIH, MMF, CIHR and FRQS.

Original languageEnglish (US)
Pages (from-to)487-500
Number of pages14
JournalEBioMedicine
Volume43
DOIs
StatePublished - May 2019

Bibliographical note

Funding Information:
This study was supported by grants from the National Institutes for Health (R21 DA020108) and the Minnesota Medical Foundation to LJK and LSS, Canadian Institutes of Health Research (CIHR) operating grants to LSS (MOP-126046), to LH and LSS (PJT-148678 and MOP-142291), and to LSS and MM (MOP-126046), and a Fonds de recherche du Qu?bec ? Sant? (FRQS) Doctoral Award to EK. The authors would like to thank Ms. Janet Moir and Ms. Lina Naso for technical support throughout the course of this project.

Funding Information:
This study was supported by grants from the National Institutes for Health ( R21 DA020108 ) and the Minnesota Medical Foundation to LJK and LSS, Canadian Institutes of Health Research (CIHR) operating grants to LSS ( MOP-126046 ), to LH and LSS ( PJT-148678 and MOP-142291 ), and to LSS and MM ( MOP-126046 ), and a Fonds de recherche du Québec – Santé (FRQS) Doctoral Award to EK. The authors would like to thank Ms. Janet Moir and Ms. Lina Naso for technical support throughout the course of this project.

Funding Information:
This study was supported by grants from the National Institutes for Health (R21 DA020108)and the Minnesota Medical Foundation to LJK and LSS, Canadian Institutes of Health Research (CIHR)operating grants to LSS (MOP-126046), to LH and LSS (PJT-148678 and MOP-142291), and to LSS and MM (MOP-126046), and a Fonds de recherche du Québec – Santé (FRQS)Doctoral Award to EK. The authors would like to thank Ms. Janet Moir and Ms. Lina Naso for technical support throughout the course of this project.

Publisher Copyright:
© 2019

Keywords

  • CXCL1
  • CXCL5
  • CXCR1/2
  • Cerebrospinal fluid
  • Intervertebral disc degeneration
  • Reparixin

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