Genotoxic stress signalling as a driver of macrophage diversity

Abstract

Tissue macrophages arise from yolk sac, fetal liver and hemato-poietic progenitors and adopt diverse transcriptional programs and phenotypes, instructed by their microenvironment. In chron-ic inflammation, such as in chronic infections, autoimmunity, or cancer, tissue microenvironments change dramatically thus im-printing new programs on tissue macrophages. While stress is a known driver of carcinogenesis in epithelial cells, emerging evi-dence suggests that macrophage responses to genotoxic stress are embedded in their ‘physiologic’ immune and tissue healing programs and in most cases do not lead to myeloid malignancies. The role of genotoxic stress as an instructor of macrophage-mediated immune defense and tissue remodeling is only begin-ning to be understood. Here, we review the evidence showing that genotoxic stress, which macrophages and their precursors face upon encountering inflammatory and/or growth signals, in-structs their transcriptional programs, by activating non-canonical, cell-type specific DNA Damage Response (DDR)-driven signaling pathways. We propose that immune-cell specific, DDR-instructed programs are crucial for tissue homeostasis as well as for the maintenance and resolution of inflammatory responses in infec-tion, cancer, autoinflammatory and autoimmune microenviron-ments.

Keywords

• dna damage
• atr
• atm
• innate immunity
• macrophage programs
• chronic inflammation