The innate immune cells known as macrophages play an important role in the coordination of regeneration, in addition to their tasks related to defense against pathogens and clearance of debris and molecular waste. Macrophages adopt different polarizations, or collections of behaviors, under different circumstances. Researchers are very interested in finding ways to force macrophages to adopt a desired polarization, such as to switch inflammatory, aggressive macrophages into a kinder, gentler pro-regeneration state. The research noted here is an example of those efforts, in that the scientists involved are attempting to make macrophages participate more readily in the regrowth of blood vessels following damage to the heart, such as that produced by a heart attack.
Despite the advent of new therapeutic strategies to restore blood flow, we are not yet able to prevent the onset of heart failure following myocardial infarction (MI). Hence, it is a major challenge to identify innovative strategies to restore nutrient supply to the infarcted myocardium, ultimately aimed at regeneration of myocardial functionality. The cellular response following MI is characterized by a rapid recruitment of neutrophils. Their arrival is superseded by the infiltration of classical monocytes, which contribute to clearance of debris. However, this subset also drives robust inflammation, leading to pathological remodeling. In contrast, the appearance of nonclassical monocytes and reparative macrophages marks a turning point between inflammation and its resolution, as these cells govern repair and angiogenesis. At this point, knowledge about mechanisms regulating this cellular switch and about origin and identity of molecular cues involved is scarce.
Annexin A1 (AnxA1) is quickly released upon cellular stress; it acts through Formyl peptide receptor-2 to prevent chemokine-mediated integrin activation, and thus, turns off inflammatory recruitment of myeloid cells. AnxA1 also activates pro-repair mechanisms by activation of Rac1 and NOX1, resulting in enhanced epithelial cell migration after injury. Local intestinal delivery of an AnxA1 fragment encapsulated within polymeric nanoparticles accelerated recovery following experimentally induced colitis. With its central position during the switch from inflammation to resolution, we hypothesized that AnxA1 may be an important cue linking initial myeloid cell recruitment to myocardial repair.
AnxA1 knockout mice showed a reduced cardiac functionality and an expansion of proinflammatory macrophages in the ischemic area. Cardiac macrophages from AnxA1 knockout mice exhibited a dramatically reduced ability to release the proangiogenic mediator vascular endothelial growth factor (VEGF)-A. However, AnxA1 treatment enhanced VEGF-A release from cardiac macrophages, and its delivery in vivo markedly improved cardiac performance. AnxA1 has a direct action on cardiac macrophage polarization toward a pro-angiogenic, reparative phenotype. AnxA1 stimulated cardiac macrophages to release high amounts of VEGF-A, thus inducing neovascularization and cardiac repair.