Genotoxic stress signalling as a driver of macrophage diversity

Abstract

Tissue macrophages arise from yolk sac, fetal liver and hematopoietic progenitors and adopt diverse transcription-al programs and phenotypes, instructed by their microenviron-ment. In chronic inflammation, such as in chronic infections, autoimmunity, or cancer, tissue microenvironments change dramatically thus imprinting new programs on tissue macro-phages. While stress is a known driver of carcinogenesis in epi-thelial cells, emerging evidence suggests that macrophage re-sponses 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 beginning 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, instructs their transcriptional programs, by activating non-canonical, cell-type specific DNA Damage Re-sponse (DDR)-driven signaling pathways. We propose that im-mune-cell specific, DDR-instructed programs are crucial for tis-sue homeostasis as well as for the maintenance and resolution of inflammatory responses in infection, cancer, autoinflammato-ry and autoimmune microenvironments.