Regulation of Macrophage Function by the Adhesive Microenvironment
Macrophages are plastic innate immune cells, involved in both inflammation and tissue repair processes. In the presence of danger signals, macrophages adopt a pro-inflammatory phenotype and secrete cytokines and reactive species to defeat infection. On the other hand, for wound healing, macrophages polarize towards a pro-healing phenotype and secrete anti-inflammatory cytokines. Modulation of macrophage behavior has emerged as a promising strategy in the design of materials used in medicine, given their prominent role in inflammation and wound healing. Although there is substantial evidence demonstrating how soluble factors such as cytokines and chemokines influence immune cell function, little is known about how physical and adhesive cues regulate macrophage behavior. While it has long been thought that biomaterial surface chemistry regulates the immune response, recent studies have suggested that material geometry may also contribute to this regulation. Our previous work demonstrated that elongation of macrophages induced their polarization towards a pro-healing phenotype. Using micropatterning technique, we demonstrated the effect of cell shape on macrophage polarization towards pro-inflammatory or pro-healing states. Macrophages forced to elongate on line substrates expressed biomarkers of pro-healing phenotype without the addition of exogenous cytokines. In this work, we examined how adhesive properties of the cellular microenvironment regulate the function of macrophages. To achieve this goal, we have demonstrated how micro- and nano-scale topographical features as well as the composition and architecture of the extracellular matrix influences macrophage adhesion and function. We found that promoting cellular elongation through surface grooves and extracellular matrix-based hydrogels enhanced pro-healing activation and inhibited the inflammatory activation of macrophages. In addition, we have demonstrated a potential underlying molecular mechanism of regulating macrophage function by adhesive microenvironment. These findings provide insight to the design of new materials to harness macrophage-mediated wound healing.