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

Si-Ping Zhang,Min Tong,Jun Mo,Zhen-yu Dong,Yi-fei Huang

Published 2025 in Journal of Orthopaedic Surgery and Research

ABSTRACT

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. 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. 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. 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. Not applicable.

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