Nrf2-dependent metabolic reprogramming in sepsis
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Host protection against infection relies on the clearance of pathogens by the immune system. In the development of sepsis, however, the immune response is dysregulated, impairs organismal metabolism and leads to multiorgan dysfunction. In contrast, tissue damage control mechanisms establish disease tolerance to infection, promoting sepsis survival without impact on pathogens. Tissue damage control mechanisms adjust the metabolic output of vital organs in response to the stress and damage imposed by infection, thereby sustaining organismal metabolism. This protective response relies on a transcriptional stress and damage response network, which establishes disease tolerance to infection. One of the core components of this network is the oxidative-stress responsive transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2). The group of Miguel Soares found that Nrf2 is critical to establish disease tolerance to malaria and to sepsis. Pharmacological compounds that activate Nrf2 might thus act therapeutically to establish disease tolerance to sepsis. Although such compounds are available, their therapeutic value is limited, because Nrf2-regulated genes impact core cellular metabolic functions, making sustained Nrf2 activation potentially detrimental. Therefore, the identification and targeting of individual Nrf2-regulated genes might capture the therapeutic value of this protective response, while avoiding its unwarranted effects. We posit that Nrf2 establishes disease tolerance to sepsis via a mechanism that acts in the liver and that a subset of Nrf2-regulated genes adjusts liver metabolic output, regulating organismal glucose metabolism and establishing disease tolerance to sepsis. While our preliminary data suggest that Nrf2 is essential to regulate this metabolic response the identity, tissue specificity and therapeutic potential of Nrf2-regulated genes driving this response is unknown and shall be established.