M2 macrophages activate the IL-10/JAK2/STAT3 pathway to induce pathological microangiogenesis in the nucleus pulposus exacerbating intervertebral disc degeneration.

Background: Macrophage infiltration accompanied by pathological microangiogenesis in the nucleus pulposus (NP) plays a critical role in the progression of intervertebral disc degeneration (IDD). However, the involvement of M2 macrophages in mediating NP pathological angiogenesis and their underlying mechanisms remain unclear.

Methods: Firstly, the expression of M2 macrophage (CD206) and microangiogenic (CD34) markers in human degenerated NP was observed by immunohistochemical staining, subsequently, a co-culture system of M2 macrophages and NP cells was established. IL-10 expression was silenced using siRNA to assess the pro-angiogenic effects of M2 macrophages in IDD via IL-10 and its downstream janus kinase (JAK) 2/ signal transducer and activator of transcription (STAT) 3 pathway. AG490, a specific JAK2/STAT3 inhibitor, was applied to determine whether IL-10 exerts its effects through this pathway and to evaluate its impact on angiogenesis and extracellular matrix (ECM) metabolism in NP pathology.

Results: CD206 and CD34 were co-expressed in degenerated NP tissue. Degenerated NP cells secreted CCL17, CCL18, and CD206, exhibiting M2-like characteristics. Co-culture of M2 macrophages with degenerated NP cells led to IL-10 secretion to promote CD34 expression, and downregulated anabolic genes (type II collagen (COL2), aggrecan), and upregulated catabolic genes (matrix metalloproteinase (MMP)-3, MMP-7). JAK2 and STAT3 expression was significantly increased following co-culture. Activation of the JAK2/STAT3 pathway enhanced vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR), and CD34 expression and induced further downregulation of COL2 and aggrecan and upregulation of MMP-3 and MMP-7.

Conclusion: M2 macrophage infiltration and pathological neovascularization are prominent in degenerated NP tissue. IL-10 secreted by M2 macrophages activates the JAK2/STAT3 pathway to promote pathological microangiogenesis by up-regulate the expression of VEGF/VEGFR. This process disrupts ECM and accelerates the progression of IDD.

Clinical Trial Number: Not applicable.