Increased serum CXCL10 levels are associated with clinical severity and radiographic progression in patients with lumbar disc degeneration

Highlights

• Serum CXCL10 concentrations were markedly raised in IDD patients with low back pain.

• Serum CXCL10 concentrations were also significantly higher in IDD patients with muscle degeneration.

• Increased CXCL10 levels positively correlated with clinical severity.

Abstract

Background

Lumbar intervertebral degenerative disc disease (IDD) is a multifaceted progressive condition that commonly occurs in conjunction with lumbar disc herniation (LDH). CXCL10 mRNA appears to be increased in both IDD and LHD.

Objective

This study was performed to identify the relationship between serum CXCL10 levels and disease severity in patients with IDD.

Methods

136 IDD patients with low back pain, 127 asymptomatic volunteers and 120 healthy controls were enrolled. Serum CXCL10 protein concentrations were detected using commercial human CXCL10 ELISA Kits. Serum CXCL10 mRNA were examined using qRT-PCR. Clinical severity was assessed using the visual analog scale (VAS) and Oswestry Disability Index(ODI) scores. Radiographic severity was defined using the MRI-based Pfirrmann classification of disc degeneration. Receiver operating characteristic (ROC) curve analysis was used in estimating the correlation between CXCL10 and Pfirrmann grade. The cross-sectional area (CSA) of the lumbar multifidus muscle (LMM) and psoas major (PM) were calculated, and fat infiltration was evaluated by Ropponen-Kjaer criteria.

Results

Serum CXCL10 concentrations were markedly raised in IDD patients with low back pain in contrast to asymptomatic individuals and healthy controls. Serum CXCL10 levels were positively associated with Pfirrmann grade. ROC curve analysis indicated that serum CXCL10 correlated well with Pfirrmann grade. In addition, serum CXCL10 concentrations were significantly higher in IDD patients with LMM and PM degeneration compared with IDD patients without degeneration. Increased CXCL10 levels positively correlated with VAS and ODI scores, as well as decreased CSA and fat filtration of the LMM and PM.

Conclusion

Increased serum CXCL10 levels correspond to clinical severity and radiographic progression in IDD patients.

Introduction

Lower back pain (LBP) afflicts approximately 70–80% of the global population at some point in their lives [1]. LBP is a significant contributor to patient morbidity and inflicts high long-term healthcare costs [2]. LBP often arises due to intervertebral disc degeneration (IDD) [3]. Despite the myriad of mechanisms, including nutrition, genetic, traumatic, and mechanical, that have been described in the degenerative process, a complete picture of how IDD develops is unclear [4], [5], [6]. IDD is typically treated with a mixture of conservative and operative approaches. Nevertheless, a large proportion of patients only manage to obtain limited degrees of symptomatic relief. Current treatment methods are unable to reverse IDD progression, with several patients remaining refractory to various therapeutic modalities [7]. Thus, a novel therapeutic target that may halt IDD development and progression is urgently needed.

Chemokines are a family of (8–12 kDa) heparin-binding messenger molecules that promote leukocyte migration [8]. Chemokines are structurally divided into 4 subfamilies: CXC, XC, CX3C, or CC [8]. Chemokines exert their biological activity by reacting with target cell surface G protein-linked transmembrane receptors [9]. Chemokines mediate several reactions such as mitogenesis, granulation, degranulation, apoptosis, organogenesis, angiogenesis, wound healing, and tissue homeostasis [10], [11], [12]. Both LDH and IDD have been found to involve chemokines in their respective disease processes. Studies have found raised systemic CCL5 and CXCL6 levels in moderate to severe LDD [13]. Elevated CX3CL1 expressions and CX3CR1-expressing cells are significantly associated with the occurrence of herniated nucleus pulposus [14]. Both CXCL12 and CCL3 are also involved in IDD progression [15], [16].

Monocytes and endothelial cells secrete C-X-C motif chemokine ligand 10 (CXCL10), also known as interferon-gamma induced protein 10 (IP-10), in retaliation to exposure to tumor necrosis factor-alpha (TNFα) and interferon-gamma (IFNγ) [17].CXCL10 exerts chemotactic effects on T lymphocytes and monocytes [18], leading to the activation of macrophages, dendritic cells, natural killer cells, as well as B and T lymphocytes [19], [20]. Various cells, especially the Th1 cell, express CXCR3, a CXCL10 receptor [21]. CXCL10/CXCR3 and its ligands are the cornerstones in the recruitment of inflammatory cells [22]. In inflamed tissues, recruited Th1 lymphocytes augment TNF-α and IFN-γ release, which go on to trigger a cascade of Th1-chemokines that serve to amplify the feedback loop[23]. Recent studies have indicated the potential role of CXCL10 in IDD development. One previous study showed that CXCL10 substantially enhances levels of annulus fibrosus cells [24]. The abundance of CXCRC in these recruited cells indicates that CXCL10 may be vital in repairing damaged annular cells [24]. Studies also demonstrated that CXCL10 is abundant in herniated disc tissue and may mediate inflammatory cell infiltration and spontaneous herniated tissue regression [25].

Interpreted as a whole, CXCL10 appears to have a key function in IDD progression. Nevertheless, there is a lack of research outlining the potential relationship between IDD disease severity and serum CXCL10 levels. We then sought to fill this knowledge gap by conducting the current study.