Macrophages Transdifferentiate Into Myofibroblasts During Ocular Surface Inflammation

Abstract

Ocular surface inflammation and injury often lead to fibrosis and impaired vision. Myofibroblasts directly promote fibrosis by producing excessive extracellular matrix (ECM) proteins and alpha-smooth muscle actin (ɑ-SMA). In addition, macrophages have been shown to promote fibrosis by secreting pro-fibrotic factors to stimulate myofibroblast formation. However, the capacity of macrophages to directly remodel ECM remains understudied. This study utilized a mouse model of corneal injury and fibrosis to determine whether macrophages transform into myofibroblast-like cells during ocular surface inflammation. Following injury, F4/80 + ɑ-SMA+ macrophages were present at the early stages of wound healing and increased in frequency and ɑ-SMA intensity during the remodeling stage. The increase in F4/80 + ɑ-SMA+ macrophages occurred due to the microenvironment transitioning from an inflammatory state to a pro-fibrotic state. Activated human and mouse macrophages treated with pro-fibrotic cytokines (IL-10 and TGF-β1) transitioned to ɑ-SMA+ macrophages, adopting a spindle-like phenotype and expressing signature myofibroblast ECM and cytoskeletal components, including ɑ-SMA, desmin, fibronectin, and collagen III. Furthermore, gel contraction assays showed ɑ-SMA+ macrophages significantly contracted a collagen gel, making them functionally resemble myofibroblasts. The results of this study indicate that macrophages have the capacity to transdifferentiate into myofibroblasts during ocular surface inflammation.