Nature and nurture of tissue-specific macrophage phenotypes.

Macrophages are key players in immunity and tissue homeostasis but can also contribute to a diverse range of human diseases, including cardiovascular diseases. Enhancers, cis-acting DNA elements regulating gene activity, have been shown to be crucial for control of macrophage development and function. The selection and activities of macrophage-specific enhancers are regulated by the combined actions of lineage determining transcription factors (LDTFs) and signal dependent transcription factors (SDTFs) that are specified by developmental origin and tissue-specific signals. As a consequence, each tissue resident macrophage population adopts a distinct phenotype. In this review, we discuss recent work on how environmental factors affect the activation status of enhancers and can lead to long-lasting epigenetic changes resulting in innate immune memory. Furthermore, we discuss how non-coding genetic variation affects gene expression by altering transcription factor binding through local and domain-wide mechanisms. These findings have implications for interpretation of non-coding risk alleles that are associated with human disease and efforts to target macrophages for therapeutic purposes.