Evolutionary Game Theory Can Explain the Choice Between Apoptotic and Necrotic Pathways in Neutrophils

Neutrophils are one of the key players in the human innate immune response. In case of an insult, neutrophils neutralize noxious pathogens via two main mechanisms: degranulation and phagocytosis. In case of a minor infection, after performing their role, neutrophils go into programmed death called apoptosis. However, if the insult is too intense, neutrophils take on a violent death pathway called necrosis, releasing their cytoplasmic content into surrounding tissue, thus aggravating inflammation. This seemingly paradoxical action is thought to fuel the inflammatory process by triggering the recruitment of additional neutrophils to the site of inflammation, possibly contributing to the complete elimination of a pathogen in case of severe infections. This delicate balance between the cost and benefit of the neutrophils' choice of death pathway has been optimized during the evolution of the innate immune system. The goal of our work is to understand how the tradeoff between the cost and benefit of the different death pathways of neutrophils in response to various levels of insults has been optimized over evolutionary time using concepts of evolutionary game theory. We show that by using evolutionary game theory, we are able to formulate a game that accurately predicts the percentage of necrosis and apoptosis when exposed to various levels of insults. By adopting an evolutionary perspective, we identify the driving mechanism leading to the delicate balance between apoptosis and necrosis in neutrophils cell death in response to different insults.