Fig. 2

Wiring diagram of the model. Injury (orange triangle) has two possible states, 0- absent, and 1- present. The response to injury occurs at two simultaneous scales, the internal cell scale (gray oval) and the extracellular tissue scale. The tissue scale initiates with production of DAMPs (purple circle) with three states, low, medium, high, and the intracellular activation of resident macrophages via the MyD88-dependent (MyD88/IRAK/NF-κB/CCL2) and -independent (CD13/TRIF/IRF3/IFN-β) pathways, resulting in recruitment of additional immune cells from the circulation (M1) and/or production of toxic ROS. The M1 node (black circle) can take on 3 states: 0, absence of macrophage activation, including resting resident macrophages; 1 standard inflammatory response- initial activation of resident macrophages and later, of recruited macrophages; and 2 exaggerated recruitment of pro-inflammatory macrophages in exacerbated injury. As the process continues, M1 macrophages become pro-healing M2 macrophages (purple circle) and dampen the pro-inflammatory response