Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
Institute for Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan.
Cell Rep. 2020 Jul 21;32(3):107938. doi: 10.1016/j.celrep.2020.107938.
Necrotic cells elicit an inflammatory response through their endogenous factors with damage-associated molecular patterns. Blocking apoptosis in Drosophila wings leads to the necrosis-driven systemic immune response by unknown mechanisms. Here, we demonstrate that immune activation in response to necrotic cells is mediated by commensal gut microbiota. Removing the microbiome attenuates hyperactivation of the innate immune signaling IMD pathway in necrosis-induced flies. Necrotic cells in wings trigger Gluconobacter expansion in the gut. An isolated Gluconobacter sp. strain is sufficient for pathological IMD activation in necrosis-induced flies, while it is not inflammatory for control animals. In addition, bacterial colonization shifts the host metabolome and shortens the lifespan of necrosis-induced flies. This study shows that local necrosis triggers a pathological systemic inflammatory response through interaction between the host and the dysbiotic gut microbiome.
坏死细胞通过其损伤相关分子模式的内源性因子引发炎症反应。在果蝇翅膀中阻止细胞凋亡会通过未知机制导致坏死驱动的全身性免疫反应。在这里，我们证明了对坏死细胞的免疫激活是由共生肠道微生物群介导的。去除微生物组可减弱坏死诱导的果蝇中先天免疫信号 IMD 途径的过度激活。翅膀中的坏死细胞触发肠道中 Gluconobacter 的扩张。一种分离的 Gluconobacter sp. 菌株足以激活坏死诱导的果蝇中病理性 IMD 的激活，而对对照动物则没有炎症作用。此外，细菌定植会改变宿主代谢组并缩短坏死诱导的果蝇的寿命。本研究表明，局部坏死通过宿主与失调的肠道微生物群之间的相互作用引发病理性全身性炎症反应。
