Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA 90095.
Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
Proc Natl Acad Sci U S A. 2022 Mar 22;119(12):e2119109119. doi: 10.1073/pnas.2119109119. Epub 2022 Mar 14.
Inflammatory response in Drosophila to sterile (axenic) injury in embryos and adults has received some attention in recent years, and most concentrate on the events at the injury site. Here we focus on the effect sterile injury has on the hematopoietic organ, the lymph gland, and the circulating blood cells in the larva, the developmental stage at which major events of hematopoiesis are evident. In mammals, injury activates Toll-like receptor/NF-κB signaling in macrophages, which then express and secrete secondary, proinflammatory cytokines. In Drosophila larvae, distal puncture injury of the body wall epidermis causes a rapid activation of Toll and Jun kinase (JNK) signaling throughout the hematopoietic system and the differentiation of a unique blood cell type, the lamellocyte. Furthermore, we find that Toll and JNK signaling are coupled in their activation. Secondary to this Toll/JNK response, a cytokine, Upd3, is induced as a Toll pathway transcriptional target, which then promotes JAK/STAT signaling within the blood cells. Toll and JAK/STAT signaling are required for the emergence of the injury-induced lamellocytes. This is akin to the derivation of specialized macrophages in mammalian systems. Upstream, at the injury site, a Duox- and peroxide-dependent signal causes the activation of the proteases Grass and SPE, needed for the activation of the Toll-ligand Spz, but microbial sensors or the proteases most closely associated with them during septic injury are not involved in the axenic inflammatory response.
近年来，人们对果蝇胚胎和成虫中无菌（无菌）损伤的炎症反应进行了一些研究，大多数研究集中在损伤部位的事件上。在这里，我们关注的是无菌损伤对造血器官、淋巴腺和幼虫血液中循环血细胞的影响，这是造血的主要事件明显发生的发育阶段。在哺乳动物中，损伤激活了巨噬细胞中的 Toll 样受体/NF-κB 信号通路，然后巨噬细胞表达和分泌二级、促炎细胞因子。在果蝇幼虫中，对体壁表皮的远端穿刺损伤导致整个造血系统中 Toll 和 Jun 激酶（JNK）信号的快速激活，并分化出一种独特的血细胞类型，即桨细胞。此外，我们发现 Toll 和 JNK 信号在其激活中是耦合的。作为 Toll 途径转录靶标的细胞因子 Upd3 随后被诱导，这随后促进了血细胞内的 JAK/STAT 信号转导。Toll 和 JAK/STAT 信号通路是损伤诱导的桨细胞出现所必需的。这类似于哺乳动物系统中专门巨噬细胞的衍生。在上游，在损伤部位，双氧化酶和过氧化物依赖性信号导致激活需要激活 Toll 配体 Spz 的蛋白酶 Grass 和 SPE，但在败血症损伤中与之最密切相关的微生物传感器或蛋白酶并不参与无菌炎症反应。
