Immunological mechanisms and immunoregulatory strategies in intervertebral disc degeneration

TL;DR

This paper reviews how immune responses contribute to intervertebral disc degeneration and discusses emerging immunotherapies, emphasizing the need for advanced research to develop effective regenerative treatments.

Contribution

It provides a comprehensive overview of immune mechanisms in IDD and introduces innovative immunoregulatory strategies, highlighting future research directions.

Findings

Immune cell infiltration and inflammation are central to IDD progression.

Novel immunotherapies like exosomes and CRISPR show therapeutic potential.

Future research should focus on immune landscape mapping and integrated therapies.

Abstract

Intervertebral discs are avascular and maintain immune privilege. However, during intervertebral disc degeneration (IDD), this barrier is disrupted, leading to extensive immune cell infiltration and localized inflammation. In degenerated discs, macrophages, T lymphocytes, neutrophils, and granulocytic myeloid-derived suppressor cells (G-MDSCs) are key players, exhibiting functional heterogeneity. Dysregulated activation of inflammatory pathways, including nuclear factor kappa-B (NF-kappaB), interleukin-17 (IL-17), and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation, drives local pro-inflammatory responses, leading to cell apoptosis and extracellular matrix (ECM) degradation. Innovative immunotherapies, including exosome-based treatments, CRISPR/Cas9-mediated gene editing, and chemokine-loaded hydrogel systems, have shown promise in reshaping the immunological niche of intervertebral discs. These strategies can modulate dysregulated immune responses and create a supportive environment for tissue regeneration. However, current studies have not fully elucidated the mechanisms of inflammatory memory and the immunometabolic axis, and they face challenges in balancing tissue regeneration with immune homeostasis. Future studies should employ interdisciplinary approaches such as single-cell and spatial transcriptomics to map a comprehensive immune atlas of IDD, elucidate intercellular crosstalk and signaling networks, and develop integrated therapies combining targeted immunomodulation with regenerative engineering, thereby facilitating the clinical translation of effective IDD treatments.