What is an M2 macrophage? Defining Macrophage-associated Causal Circuits in Type 2 Settings

Currently, the gold standard to study macrophage biology in vivo relies on CRE-lox technology, to generate cell-specific knockouts, a time-consuming process that requires high numbers of animals. Unfortunately, the in vitro or in silico data used to select genes for investigation, often fail to replicate in vivo biology. The enormous plasticity of these cells means that identifying the causal circuits that control macrophage activation in vivo seems unachievable. This challenge is exemplified by macrophages with anti-inflammatory, wound reparative and/or anti-helminthic properties, often classed as M2-macrophages. There is not a straightforward transcriptional profile that defines the vast range of cells exhibiting these related properties. While IL-4-receptor signaling is considered a key driver of M2 activation, it is often not sufficient or even necessary. It would take decades using standard KO technologies to filter through the multitude of factors, including tissue-specific signals, and unravel the molecular circuits that define an M2 macrophage. However, development of pooled CRISPR screens with novel computational methods now brings this goal within reach. We will apply these approaches to macrophages in type 2 settings, redefining the M2 paradigm at unprecedented speed. Sharing our findings and tools with the community will open a new era in macrophage biology.