Abstract
A binary classification of macrophage activation as inflammatory or resolving does not capture the diversity of macrophage states observed in tissues. However, framing macrophage activation as a continuous spectrum of states overlooks the intracellular and extracellular networks that regulate and coordinate macrophage responses. Here, we suggest that the systems biology concept of network motifs, which incorporate rules of local molecular interactions, is useful for reframing macrophage activation. Because network motifs can be used to regulate distinct biological functions, they offer a simplified unit that can be compared across organismal, tissue, and disease contexts. Moreover, defining macrophage states as combinations of functional modules regulated by network motifs offers a framework to ultimately predict and target macrophage responses arising in complex environments.