Heterogeneous macrophages contribute to the pathology of disc herniation induced radiculopathy

Abstract

Background context: Macrophages play important roles in the progression of intervertebral disc herniation and radiculopathy.

Purpose: To better understand the roles of macrophages in this process, we developed a new mouse model that mimics human radiculopathy.

Study design/setting: A preclinical randomized animal study.

Methods: Three types of surgeries were performed in randomly assigned Balb/c mice. These were spinal nerve exposure, traditional anterior disc puncture, and lateral disc puncture with nerve exposure (n=16/group). For the nerve exposure group, the left L5 spinal nerve was exposed without disc injury. For the traditional anterior puncture, L5/6 disc was punctured by an anterior approach as previously established. For lateral puncture with nerve exposure, the left L5 spinal nerve was exposed by removing the psoas major muscle fibers, and the L5/6 disc was punctured laterally on the left side with a 30G needle, allowing the nucleus to protrude toward the L5 spinal nerve. Mechanical hyperalgesia (pain sensitivity) of hind paws was assessed with electronic von Frey assay on alternative day for up to 2 weeks. MRI, histology, and immunostaining were performed to confirm disc herniation and inflammation.

Results: Ipsilateral pain in the lateral puncture with nerve exposure group was significantly greater than the other groups. Pro-inflammatory cytokines IL-1β and IL-6 were markedly elevated at the hernia sites of both puncture groups and the spinal nerve of lateral puncture with never exposure group on postoperative day 7. Heterogeneous populations of macrophages were detected in the infiltration tissue of this mouse model and in tissue from patients undergone discectomy.

Conclusions: We have established a new mouse model that mimics human radiculopathy and demonstrated that a mixed phenotype of macrophages contribute to the pathogenesis of acute discogenic radiculopathy.

Clinical significance: This study provides a clinically relevant in vivo animal model to elucidate complex interactions of disc herniation and radicular pain, which may present opportunities for the development of macrophage-anchored therapeutics to manage radiculopathy.

Keywords: Animal model; Disc Degeneration; Disc herniation; Inflammation; Low back pain; Macrophages; Radiculopathy.