Kasapi Ana, Triantafyllopoulou Antigoni
Department of Rheumatology and Clinical Immunology and Institute of Microbiology, Charité University Medical Center, D-10117 Berlin, Germany.
German Rheumatism Research Center, a Leibniz Institute, D-10117 Berlin, Germany.
Cell Stress. 2022 Feb 14;6(3):30-44. doi: 10.15698/cst2022.03.265. eCollection 2022 Mar.
Tissue macrophages arise from yolk sac, fetal liver and hematopoietic progenitors and adopt diverse transcriptional programs and phenotypes, instructed by their microenvironment. In chronic inflammation, such as in chronic infections, autoimmunity, or cancer, tissue microenvironments change dramatically thus imprinting new programs on tissue macrophages. While stress is a known driver of carcinogenesis in epithelial cells, emerging evidence 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 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 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 infection, cancer, autoinflammatory and autoimmune microenvironments.
组织巨噬细胞起源于卵黄囊、胎儿肝脏和造血祖细胞，并在其微环境的指导下采用多种转录程序和表型。在慢性炎症中，如慢性感染、自身免疫或癌症，组织微环境会发生巨大变化，从而在组织巨噬细胞上印记新的程序。虽然应激是上皮细胞致癌的已知驱动因素，但新出现的证据表明，巨噬细胞对基因毒性应激的反应嵌入其“生理”免疫和组织修复程序中，在大多数情况下不会导致髓系恶性肿瘤。基因毒性应激作为巨噬细胞介导的免疫防御和组织重塑的指导者的作用才刚刚开始被理解。在这里，我们回顾了证据，表明巨噬细胞及其前体在遇到炎症和/或生长信号时所面临的基因毒性应激，通过激活非经典的、细胞类型特异性的DNA损伤反应（DDR）驱动的信号通路来指导其转录程序。我们提出，免疫细胞特异性的、DDR指导的程序对于组织稳态以及感染、癌症、自身炎症和自身免疫微环境中炎症反应的维持和消退至关重要。
