Nature and nurture of tissue-specific macrophage phenotypes

• Published in: Atherosclerosis Vol. 281; pp. 159 - 167
• Main Authors: Hoeksema, Marten A., Glass, Christopher K.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.02.2019
• Subjects: Animals; Cell Plasticity - genetics; Cellular Microenvironment; Enhancer; Epigenesis, Genetic; Gene-Environment Interaction; Genetic variation; Humans; Immunity, Innate - genetics; Immunologic Memory - drug effects; Macrophage; Macrophage Activation - genetics; Macrophages - immunology; Macrophages - metabolism; Signal Transduction; Tissue environment; Transcription, Genetic; Enhancer; Genetic variation; Tissue environment; Macrophage
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2018.10.005

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. •Macrophage enhancers are selected as a result of origin and tissue signals.•Selection of enhancer differences result in tissue-specific macrophage phenotypes.•Danger signals result in long-term epigenetic changes leading to immune memory.•Genetic variation alters enhancer selection and activation.