The inflammatory response in the regression of lumbar disc herniation

Abstract

Lumbar disc herniation (LDH) is highly associated with inflammation in the context of low back pain. Currently, inflammation is associated with adverse symptoms related to the stimulation of nerve fibers that may lead to pain. However, inflammation has also been indicated as the main factor responsible for LDH regression. This apparent controversy places inflammation as a good prognostic indicator of spontaneous regression of LDH. This review addresses the molecular and cellular mechanisms involved in LDH regression, including matrix remodeling and neovascularization, in the scope of the clinical decision on conservative versus surgical intervention. Based on the evidence, a special focus on the inflammatory response in the LDH context is given, particularly in the monocyte/macrophage role. The phenomenon of spontaneous regression of LDH, extensively reported in the literature, is therefore analyzed here under the perspective of the modulatory role of inflammation.

Keywords: Immunomodulation; Intervertebral disc; Low back pain; Macrophages; Spine.

Fig. 1

a Schematic representation of typical L4–L5 hernia, with compression and possible rupture of posterior longitudinal ligament (PLL). b Human LDH fragment, obtained from patient who underwent microdiscectomy after informed consent and ethics committee approval from Centro Hospitalar São João. c Histological staining of tissue collected in (b), showing cell clusters producing proteoglycans (Alcian blue) embedded in a collagen matrix (Picrosirius red). d LDH is currently divided into four subtypes, according to MRI, as bulging disc (mildest form), protrusion, extrusion, and sequestration, the severest form of LDH. Proteoglycan-rich nucleus pulposus in center is surrounded by collagen-rich concentric rings of annulus fibrosus. Scale bars: (b) 3 cm, (c) 100 μm. Image credits: (a, d) used elements from Servier Medical Art; (b, c) unpublished

Fig. 2

Representative proposed mechanism of LDH resorption. Both herniated IVD tissue and macrophages produce tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein (MCP)-1, matrix metalloproteinases (MMPs), interleukin (IL)-6, IL-8, prostaglandin E2 (PGE2), cyclooxygenase 2 (COX2), and nitric oxide (NO), which contribute to the inflammatory reaction and resorption of the herniated tissue. Vascular endothelial growth factor (VEGF) induces blood vessel ingrowth and neovascularization, which support immune cell mobilization to hernia site. Insert: in rat model of IVD herniation, CD68⁺ macrophages localized within hernia (delimitated by dashed line), which include a blood vessel (arrow). Scale bar: 100 μm. Image used elements from Servier Medical Art; insert: unpublished