Fig. 1

Scheme of the innate immune response to injury. Injury triggers the production of DAMPs in the tissue that activate intracellular responses via TLR4, initially in the resident macrophages and later from recruited macrophages (large gray oval). TLR4 activation stimulates two intracellular pathways, the MyD88-dependent (blue rectangles), resulting in production and secretion of the chemoattractant CCL2 which serves to recruit additional immune cells from the circulation (right). In response to CCL2, M1 monocytes leave the circulation and enter the tissue where they differentiate into pro-inflammatory M1 macrophages that clear toxic debris and become activated to produce more CCL2, perpetuating the inflammatory response. TLR4 can also signal via a MyD88-independent endocytic pathway (center left) that is mediated by CD13, TRIF and IRF3. Increased activation of this pathway can lead to production of cell-damaging ROS and increased DAMPs. Finally, M1 macrophages convert into pro-healing M2 macrophages which dampen the pro-inflammatory response by blocking production of CCL2 and DAMPs, leading to resolution