Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, VIC, Australia.
Cell. 2019 Apr 4;177(2):399-413.e12. doi: 10.1016/j.cell.2019.01.050. Epub 2019 Mar 7.
Host defenses against pathogens are energetically expensive, leading ecological immunologists to postulate that they might participate in energetic trade-offs with other maintenance programs. However, the metabolic costs of immunity and the nature of physiologic trade-offs it engages are largely unknown. We report here that activation of immunity causes an energetic trade-off with the homeothermy (the stable maintenance of core temperature), resulting in hypometabolism and hypothermia. This immunity-induced physiologic trade-off was independent of sickness behaviors but required hematopoietic sensing of lipopolysaccharide (LPS) via the toll-like receptor 4 (TLR4). Metabolomics and genome-wide expression profiling revealed that distinct metabolic programs supported entry and recovery from the energy-conserving hypometabolic state. During bacterial infections, hypometabolic states, which could be elicited by competition for energy between maintenance programs or energy restriction, promoted disease tolerance. Together, our findings suggest that energy-conserving hypometabolic states, such as dormancy, might have evolved as a mechanism of tissue tolerance.
宿主防御病原体的能力需要消耗大量能量，这使得生态免疫学家推测，宿主可能会在能量层面与其他维持程序进行权衡。然而，免疫的代谢成本以及它所涉及的生理权衡的性质在很大程度上仍是未知的。我们在这里报告称，免疫的激活会导致与体温调节（核心温度的稳定维持）的能量权衡，从而导致代谢率降低和体温降低。这种免疫诱导的生理权衡与疾病行为无关，但需要通过 Toll 样受体 4（TLR4）感知造血细胞对脂多糖（LPS）的反应。代谢组学和全基因组表达谱分析显示，不同的代谢程序支持进入和从节能低代谢状态中恢复。在细菌感染期间，低代谢状态（可能是由于维持程序或能量限制之间的能量竞争引起的）可以促进疾病耐受。总之，我们的发现表明，节能低代谢状态，如休眠，可能是作为组织耐受的一种机制而进化出来的。
