Important role of mechanical microenvironment on macrophage dysfunction during keloid pathogenesis

Keloid is considered as a tumor-like skin disease with multiple aetiologies including immunological factors and mechanical microenvironment. Macrophages are plastic and diverse immune cells that play a critical role in maintaining tissue homeostasis by removing dead cells, debris, pathogens and repairing tissues after inflammation. The imbalance of M1/M2 macrophages and disturbances in macrophage functions can steer the progression of chronic inflammation and lead to the development of pathological fibrosis in keloid disease. Recently, it has been shown that macrophages are sensitive to mechanical signals, especially stretching tension and tissue stiffness, which can determine macrophage polarization and functions. Higher stretching tension is known to be an important pathogenic factor of keloid, and the formation of keloid will lead to an increase in tissue stiffness. As little is known about the underlying reasons of macrophages dysfunction in keloid, an understanding of how the mechanical microenvironment interacting with macrophages and affecting their behaviours may help provide mechanism insights into keloid pathogenesis. We thus hypothesize that the synergistic effect of stretching tension and matrix stiffness may contribute to the major pathophysiological niche attributes of macrophages' in vivo mechanical microenvironment in keloids. These mechanism insights of how macrophages sense and respond to their mechanical microenvironment would propel the development of novel strategies for keloid treatment.