B cell-derived GABA elicits IL-10+ macrophages to limit anti-tumour immunity

Small, soluble metabolites not only are essential intermediates in intracellular biochemical processes, but can also influence neighbouring cells when released into the extracellular milieu1–3. Here we identify the metabolite and neurotransmitter GABA as a candidate signalling molecule synthesized and secreted by activated B cells and plasma cells. We show that B cell-derived GABA promotes monocyte differentiation into anti-inflammatory macrophages that secrete interleukin-10 and inhibit CD8+ T cell killer function. In mice, B cell deficiency or B cell-specific inactivation of the GABA-generating enzyme GAD67 enhances anti-tumour responses. Our study reveals that, in addition to cytokines and membrane proteins, small metabolites derived from B-lineage cells have immunoregulatory functions, which may be pharmaceutical targets allowing fine-tuning of immune responses.

Lactate Metabolism Regulates Tumour Growth and Progression in Glioblastoma

Background. Tumor microenvironment (TME) plays a pivotal role in establishing malignancy and it is associated with high glycolytic metabolism and increased lactate production accumulating in TME through monocarboxylate transporters (MCTs). Several lines of evidence suggest that lactate also serves as a signalling molecule through its receptor HCAR1thus functioning as a paracrine and autocrine signalling molecule in TME. The aim of the present study was to investigate the role of lactate in glioblastoma (GBM) progression and metabolic reprogramming in an in vitro and in vivo model.Methods. Cell proliferation, migration and clonogenicity assay were performed in vitro on three different human GBM cell lines. Protein expression of MCT1, MCT4 and pharmacological lactate receptor (GPR81) were evaluated both in vitro and in a zebrafish GBM in vivo model. These results were further validated in patient-derived GBM biopsies.Results. Our results showed that lactate significantly increased cell proliferation, migration and colony formation capacity of GBM cells, both in vitro and in vivo. We also showed that lactate increased MCT1 and HCAR1 expression. Moreover, lactate modulated epithelial-mesenchymal transition protein markers E-Cadherin and β-Catenin. Interestingly, lactate induced mitochondrial mass and OXPHOS gene suggesting an improved mitochondrial fitness. Similar effects were observed after treatment with 3,5-Dihydroxybenzoic acid, a known agonist of GPR81. Consistently, GBM zebrafish model exhibited an altered metabolism and increased expression of MCT1 and HCAR1 leading to high levels of extracellular lactate and thus supporting tumor cell proliferation. Our data from human GBM biopsies also showed that in high proliferative GBM biopsies, Ki67 positive cells expressed significantly higher levels of MCT1 compared to low proliferative GBM cells.Conclusions. Our data suggest that lactate favours proliferation of neighbourhood cells by cooperating with their glycolytic metabolism, sensing and removing extracellular lactate. In particular, lactate and its transporter and receptor play a major role in GBM proliferation and migration thus representing a potential target to develop new strategies to counteract tumor progression and recurrencies.

Diversity of the Tryptophanase Gene and Its Evolutionary Implications in Living Organisms

Tryptophanase encoded by the gene tnaA is a pyridoxal phosphate-dependent enzyme that catalyses the conversion of tryptophan to indole, which is commonly used as an intra- and interspecies signalling molecule, particularly by microbes. However, the production of indole is rare in eukaryotic organisms. A nucleotide and protein database search revealed tnaA is commonly reported in various Gram-negative bacteria, but that only a few Gram-positive bacteria and archaea possess the gene. The presence of tnaA in eukaryotes, particularly protozoans and marine organisms, demonstrates the importance of this gene in the animal kingdom. Here, we document the distribution of tnaA and its acquisition and expansion among different taxonomic groups, many of which are usually categorized as non-indole producers. This study provides an opportunity to understand the intriguing role played by tnaA, and its distribution among various types of organisms.

Sterols, Oxysterols, and Accessible Cholesterol: Signalling for Homeostasis, in Immunity and During Development

In this article we discuss the concept of accessible plasma membrane cholesterol and its involvement as a signalling molecule. Changes in plasma membrane accessible cholesterol, although only being minor in the context of total cholesterol plasma membrane cholesterol and total cell cholesterol, are a key regulator of overall cellular cholesterol homeostasis by the SREBP pathway. Accessible cholesterol also provides the second messenger between patched 1 and smoothened in the hedgehog signalling pathway important during development, and its depletion may provide a mechanism of resistance to microbial pathogens including SARS-CoV-2. We revise the hypothesis that oxysterols are a signalling form of cholesterol, in this instance as a rapidly acting and paracrine version of accessible cholesterol.

Hydrogen sulfide in ageing, longevity and disease

Hydrogen sulfide (H2S) modulates many biological processes, including ageing. Initially considered a hazardous toxic gas, it is now recognised that H2S is produced endogenously across taxa and is a key mediator of processes that promote longevity and improve late-life health. In this review, we consider the key developments in our understanding of this gaseous signalling molecule in the context of health and disease, discuss potential mechanisms through which H2S can influence processes central to ageing and highlight the emergence of novel H2S-based therapeutics. We also consider the major challenges that may potentially hinder the development of such therapies.

Much more than a toxin: hydrogen cyanide is a volatile modulator of bacterial behaviour

Bacteria communicate with each other and with other organisms in a chemical language comprising both diffusible and volatile molecules, and volatiles have recently gained increasing interest as mediators of bacterial interactions. One of the first volatile compounds discovered to play a role in biotic interactions is hydrogen cyanide (HCN), a well-known toxin, which irreversibly binds to the key respiratory enzyme cytochrome C oxidase. The main ecological function of this molecule was so far thought to lie in the inhibition of competing microorganisms. Here we show that HCN is much more than a respiratory toxin and should be considered a major regulator of bacterial behaviour rather than a solely defensive secondary metabolite. Cyanogenesis occurs in both environmental and clinical Pseudomonas strains. Using cyanide-deficient mutants in two Pseudomonas strains, we demonstrate that HCN functions as an intracellular and extracellular volatile signalling molecule, which leads to global transcriptome reprogramming affecting growth, motility, and biofilm formation, as well as the production of other secondary metabolites such as siderophores and phenazines. Our data suggest that bacteria are not only using endogenous HCN to control their own cellular functions, but are also able to remotely influence the behaviour of other bacteria sharing the same environment.

Elucidation of sub-cellular H2S metabolism in Solanum lycopersicum L. and its assessment under development and biotic stress

The signalling molecules serve as a fundamental requirement in plants and respond to various internal and external cues. Among several signalling molecules, the significance of gasotransmitters has been realized in several plant developmental and environmental constraints. The hydrogen sulfide (H2S) is a novel signalling molecule in higher plants and is involved in several physiological processes right from seed germination to flowering and fruit ripening. Moreover, H2S also assist plants in managing biotic and abiotic stresses, therefore serves as one of the imperative choice of chemical priming. Yet, the metabolism of H2S is not much explored and only appraisal study is made till date from Arabidopsis thaliana. Therefore, the present investigation explored the elucidation of H2S metabolism in crop plant Solanum lycopersicum L. Through in silico investigations the study demonstrated the participation of 29 proteins involved in H2S metabolism, which are mainly localized in cytosol, chloroplast, and mitochondria. Additionally, the relevant protein-protein interactomes were also inferred for sub-cellular compartments and expression data were explored under development and biotic stresses namely PAMPs treatment and bacterial infection. The information generated here will be of high relevance to better target the H2S metabolism to enhance the tomato prospects and also serve a preliminary investigation to be adopted in other agronomic important crops.

Lactate cross-talk in host–pathogen interactions

Lactate is the main product generated at the end of anaerobic glycolysis or during the Warburg effect and its role as an active signalling molecule is increasingly recognised. Lactate can be released and used by host cells, by pathogens and commensal organisms, thus being essential for the homeostasis of host–microbe interactions. Infection can alter this intricate balance, and the presence of lactate transporters in most human cells including immune cells, as well as in a variety of pathogens (including bacteria, fungi and complex parasites) demonstrates the importance of this metabolite in regulating host–pathogen interactions. This review will cover lactate secretion and sensing in humans and microbes, and will discuss the existing evidence supporting a role for lactate in pathogen growth and persistence, together with lactate's ability to impact the orchestration of effective immune responses. The ubiquitous presence of lactate in the context of infection and the ability of both host cells and pathogens to sense and respond to it, makes manipulation of lactate a potential novel therapeutic strategy. Here, we will discuss the preliminary research that has been carried out in the context of cancer, autoimmunity and inflammation.