Tryptophol Acetate and Tyrosol Acetate, Small-Molecule Metabolites Identified in a Probiotic Mixture, Inhibit Hyperinflammation.

Probiotic fermented foods are perceived as contributing to human health; however, solid evidence for their presumptive therapeutic systemic benefits is generally lacking. Here we report that tryptophol acetate and tyrosol acetate, small-molecule metabolites secreted by the probiotic milk-fermented yeast Kluyveromyces marxianus, inhibit hyperinflammation (e.g., "cytokine storm"). Comprehensive in vivo and in vitro analyses, employing LPS-induced hyperinflammation models, reveal dramatic effects of the molecules, added in tandem, on mice morbidity, laboratory parameters, and mortality. Specifically, we observed attenuated levels of the proinflammatory cytokines IL-6, IL-1α, IL-1ß, and TNF-α and reduced reactive oxygen species. Importantly, tryptophol acetate and tyrosol acetate did not completely suppress proinflammatory cytokine generation, rather brought their concentrations back to baseline levels, thus maintaining core immune functions, including phagocytosis. The anti-inflammatory effects of tryptophol acetate and tyrosol acetate were mediated through downregulation of TLR4, IL-1R, and TNFR signaling pathways and increased A20 expression, leading to NF-kB inhibition. Overall, this work illuminates phenomenological and molecular details underscoring anti-inflammatory properties of small molecules identified in a probiotic mixture, pointing to potential therapeutic avenues against severe inflammation.

Heat stress increases immune cell function in Hexacorallia.

Climate change induced heat stress has increased coral bleaching events worldwide. Differentially regulated immune genes are one of the primary responses to heat stress suggesting that immune activation is critical. However, the cellular immune mechanisms of coral bleaching is currently unknown, and it is still not known if the immune response documented during heat stress is a consequence of bleaching or is directly caused by the heat stress itself. To address this question, we have used two model system sea anemones (Order: Actiniaria): Exaiptasia diaphana and Nematostella vectensis. E. diaphana is an established sea anemone model for algal symbiont interaction, while N. vectensis is an established sea anemone model that lacks the algal symbiont. Here, we examined the effect of increased temperature on phagocytic activity, as an indication of immune function. Our data shows that immune cell activity increases during heat stress, while small molecule pinocytosis remains unaffected. We observed an increase in cellular production of reactive oxygen species with increasing temperatures. We also found that the cellular immune activity was not affected by the presence of the Symbiodiniaceae. Our results suggest that the immune activity observed in heat-stress induced bleaching in corals is a fundamental and basic response independent of the bleaching effect. These results establish a foundation for improving our understanding of hexacorallian immune cell biology, and its potential role in coral bleaching.

Evolution of Cellular Immunity Effector Cells; Perspective on Cytotoxic and Phagocytic Cellular Lineages.

The immune system has evolved to protect organisms from infections caused by bacteria, viruses, and parasitic pathogens. In addition, it provides regenerative capacities, tissue maintenance, and self/non-self recognition of foreign tissues. Phagocytosis and cytotoxicity are two prominent cellular immune activities positioned at the base of immune effector function in mammals. Although these immune mechanisms have diversified into a wide heterogeneous repertoire of effector cells, it appears that they share some common cellular and molecular features in all animals, but also some interesting convergent mechanisms. In this review, we will explore the current knowledge about the evolution of phagocytic and cytotoxic immune lineages against pathogens, in the clearance of damaged cells, for regeneration, for histocompatibility recognition, and in killing virally infected cells. To this end, we give different immune examples of multicellular organism models, ranging from the roots of bilateral organisms to chordate invertebrates, comparing to vertebrates' lineages. In this review, we compare cellular lineage homologies at the cellular and molecular levels. We aim to highlight and discuss the diverse function plasticity within the evolved immune effector cells, and even suggest the costs and benefits that it may imply for organisms with the meaning of greater defense against pathogens but less ability to regenerate damaged tissues and organs.