Letters

Homology between the mammalian liver and the Drosophila fat body

The goal of PrecisionTox is to overcome conceptual barriers to replacing traditional mammalian chemical safety testing by accelerating the discovery of evolutionarily conserved toxicity pathways that are shared by descent among humans and more distantly related animals. An international consortium is systematically testing the toxicological effects of a diverse set of chemicals on a suite of five model species comprising fruit flies, nematodes, water fleas, and embryos of clawed frogs and zebrafish along with human cell lines. Multiple forms of omics and comparative toxicology data are integrated to map the evolutionary origins of biomolecular interactions that are predictive of adverse health effects, to major branches of the animal phylogeny. These conserved elements of adverse outcome pathways (AOPs) and their biomarkers are expected to provide mechanistic insight useful for regulating groups of chemicals based on their shared modes of action. PrecisionTox also aims to quantify risk variation within populations by recognizing susceptibility as a heritable trait that varies with genetic diversity. This initiative incorporates legal experts and collaborates with risk managers to address specific needs within European chemicals legislation, including the uptake of new approach methodologies (NAMs) for setting precise regulatory limits on toxic chemicals.

Compelling experimental evidence links immunity and metabolism. In this perspective, we propose forkhead-box-P3 (FoxP3)⁺CD4⁺CD25⁺ regulatory T (Treg) cells as key metabolic sensors controlling the immunological state in response to their intrinsic capacity to perceive nutritional changes. Treg cell high anabolic state in vivo, residency in metabolically crucial districts, and recirculation between lymphoid and non-lymphoid sites enable them to recognize the metabolic cues and adapt their intracellular metabolism and anti-inflammatory function at the paracrine and systemic levels. As privileged regulators at the interface between neuroendocrine and immune systems, the role of Treg cells in maintaining metabolic homeostasis makes these cells promising targets of therapeutic strategies aimed at restoring organismal homeostasis not only in autoimmune but also metabolic disorders.

Many studies have suggested a role for gut-resident microbes (the “gut microbiome”) in modulating host health; however, the mechanisms by which they impact systemic physiology remain largely unknown. In this study, metabolomic and transcriptional profiling of germ-free and conventionalized mouse liver revealed an upregulation of the Nrf2 antioxidant and xenobiotic response in microbiome-replete animals. Using a Drosophila-based screening assay, we identified members of the genus Lactobacillus capable of stimulating Nrf2. Indeed, the human commensal Lactobacillus rhamnosus GG (LGG) potently activated Nrf2 in the Drosophila liver analog and the murine liver. This activation was sufficient to protect against two models of oxidative liver injury, acetaminophen overdose and acute ethanol toxicity. Characterization of the portal circulation of LGG-treated mice by tandem mass spectrometry identified a small molecule activator of Nrf2, 5-methoxyindoleacetic acid, produced by LGG. Taken together, these data demonstrate a mechanism by which intestinal microbes modulate hepatic susceptibility to oxidative injury.

The inexorable emergence of mosquito-borne arboviruses and the failure of traditional vector control methods to prevent their transmission have triggered the development of alternative entomological interventions to render mosquito populations incapable of carrying arboviruses. Here, we use a theoretical framework to argue that decreasing mosquito tolerance to arbovirus infection could be a more evolutionarily sustainable disease control strategy than increasing mosquito resistance. Increasing resistance is predicted to select for mutant arboviruses escaping resistance, whereas reducing tolerance should lead to the death of infected vectors and thus select for mosquito-attenuated arbovirus variants that are less transmissible.

Adipose tissue plays an important role in energy reservation, also be considered as vital immunological organ in animals. Adipocytes are the basic unit of adipose tissue, while little is known about the relationship between lipid metabolism and inflammatory response in fish adipocytes so far. In this study, forskolin was used to induce adipocyte lipolysis, and 5 μM forskolin and 30 μM forskolin both triggered lipolysis by increasing ATGL expression. Consequently, 30 μM Forskolin instead of 5 μM Forskolin induced the expression of NF-κB and its target pro-inflammatory cytokine genes including MCP-1, IL-6 and TNF-α. Further study found that low grade rate of lipolysis activated PPARα gene, and its inhibitory effect on the mRNA expression of NF-κB and its target genes inhibited the adipocyte inflammation. On the contrary, high grade rate of lipolysis increased the expression levels of NF-κB and its target genes, while their expression were attenuated by inhibition of reactive oxygen species (ROS) using α-tocopherol, suggesting that ROS generated due to the PPARα-mediated oxidation of released fatty acids from lipolysis may contribute to adipocyte inflammation. These results indicated that PPARα has dose effect in inflammatory responses to adipocyte lipolysis in grass carp. Taken together, grass carp adipocytes have immune activity. The inflammatory response is linked to the grade rate of adipocyte lipolysis in grass carp adipocytes, and excessive adipocyte lipolysis may promote a dynamic immune response in adipose tissue. This is the first study showing the regulatory effects of lipolysis on immune functions in fish adipocytes.

Iron metabolism is an essential process that when dysregulated causes disease. Mammalian serum transferrin (TF) plays a primary role in delivering iron to cells. To improve our understanding of the conservation of iron metabolism between species, we investigate here the function of the TF homolog in Drosophila melanogaster, transferrin 1 (Tsf1). Tsf1 knockdown results in iron accumulation in the gut and iron deficiency in the fat body (which is analogous to the mammalian liver). Fat body-derived Tsf1 localizes to the gut surface, suggesting that Tsf1 functions in trafficking iron between the gut and the fat body, similar to TF in mammals. Moreover, Tsf1 knockdown strongly suppresses the phenotypic effects of ferritin (Fer1HCH) RNAi, an established iron trafficker in Drosophila. We propose that Tsf1 and ferritin compete for iron in the Drosophila intestine and demonstrate the value of using Drosophila for investigating iron trafficking and the evolution of systemic iron regulation.