M2 Macrophage-Derived TGF-β1 Drives Tendon Fibrosis in Rodent Tendinopathy Models.

Abstract

Tendinopathy is a common degenerative tendon disorder, characterized by extracellular matrix disorganization and progressive fibrosis. While macrophages play a role in fibrosis in other tissues, their specific function in tendon fibrosis remains unclear. This study aims to investigate the involvement of M2-polarized macrophages and their secretion of transforming growth factor-β1 (TGF-β1) in tendon fibrosis. A chronic Achilles tendinopathy rat model was established by combining repetitive acupuncture needle puncture with treadmill overuse. Immunofluorescence and molecular biology techniques were used to assess M2 macrophage infiltration, TGF-β1 expression, and JNK pathway activation. Pharmacological intervention was performed using GW2580 (CSF-1R antagonist), and genetic knockout experiments were conducted in a mouse model. Results showed that the model group exhibited disrupted collagen structure and fibrotic matrix deposition in the tendon, accompanied by significant accumulation of CD206⁺ M2 macrophages and elevated TGF-β1 expression. Immunofluorescence co-localization revealed that TGF-β1 was primarily produced by CD206⁺ macrophages. Activation of the JNK signaling pathway was observed. GW2580 treatment significantly reduced M2 macrophage infiltration, suppressed TGF-β1 levels, and improved histological fibrosis scores. Genetic deletion of Tgf-β1 in myeloid cells also alleviated fibrotic changes. In conclusion, M2 macrophage-derived TGF-β1 plays a crucial role in tendon fibrosis by activating the JNK signaling pathway, suggesting its potential as a therapeutic target.