Expression and function of odorant receptors (ORs), which account for more than 50% of G protein–coupled receptors, are being increasingly reported in nonolfactory sites. However, ORs that can be targeted by drugs to treat diseases remain poorly identified. Tumor-derived lactate plays a crucial role in multiple signaling pathways leading to generation of tumor-associated macrophages (TAMs). In this study, we hypothesized that the macrophage OR Olfr78 functions as a lactate sensor and shapes the macrophage–tumor axis. Using Olfr78+/+ and Olfr78−/− bone marrow–derived macrophages with or without exogenous Olfr78 expression, we demonstrated that Olfr78 sensed tumor-derived lactate, which was the main factor in tumor-conditioned media responsible for generation of protumoral M2-TAMs. Olfr78 functioned together with Gpr132 to mediate lactate-induced generation of protumoral M2-TAMs. In addition, syngeneic Olfr78-deficient mice exhibited reduced tumor progression and metastasis together with an increased anti- versus protumoral immune cell population. We propose that the Olfr78–lactate interaction is a therapeutic target to reduce and prevent tumor progression and metastasis.

Odorant receptors (ORs), the largest subfamily of G proteincoupled receptors, detect odorants in the nose. In addition, ORs were recently shown to be expressed in many nonolfactory tissues and cells, indicating that these receptors have physiological and pathophysiological roles beyond olfaction. Many ORs are expressed by tumor cells and tissues, suggesting that they may be associated with cancer progression or may be cancer biomarkers. This review describes OR expression in various types of cancer and the association of these receptors with various types of signaling mechanisms. In addition, the clinical relevance and significance of the levels of OR expression were evaluated. Namely, levels of OR expression in cancer were analyzed based on RNA-sequencing data reported in the Cancer Genome Atlas; OR expression patterns were visualized using t-distributed stochastic neighbor embedding (t-SNE); and the associations between patient survival and levels of OR expression were analyzed. These analyses of the relationships between patient survival and expression patterns obtained from an open mRNA database in cancer patients indicate that ORs may be cancer biomarkers and therapeutic targets. [BMB Reports 2022; 55(2): 72-80]

Microglia (MG), the principal neuroimmune sentinels in the brain, continuously sense changes in their environment and respond to invading pathogens, toxins, and cellular debris, thereby affecting neuroinflammation. Microbial pathogens produce small metabolites that influence neuroinflammation, but the molecular mechanisms that determine whether pathogen‐derived small metabolites affect microglial activation of neuroinflammation remain to be elucidated. We hypothesized that odorant receptors (ORs), the largest subfamily of G protein‐coupled receptors, are involved in microglial activation by pathogen‐derived small metabolites. We found that MG express high levels of two mouse ORs, Olfr110 and Olfr111, which recognize a pathogenic metabolite, 2‐pentylfuran, secreted by Streptococcus pneumoniae. These interactions activate MG to engage in chemotaxis, cytokine production, phagocytosis, and reactive oxygen species generation. These effects were mediated through the Gαs–cyclic adenosine monophosphate–protein kinase A–extracellular signal‐regulated kinase and Gβγ–phospholipase C–Ca2+ pathways. Taken together, our results reveal a novel interplay between the pathogen‐derived metabolite and ORs, which has major implications for our understanding of microglial activation by pathogen recognition. Database Model data are available in the PMDB database under the accession number PM0082389.

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Pseudomonas aeruginosa ( P. aeruginosa ) is a well-known Gram-negative opportunistic pathogen. Neutrophils play key roles in mediating host defense against P. aeruginosa infection. In this study, we identified a metabolite derived from P. aeruginosa that regulates neutrophil activities. Using gas chromatography-mass spectrometry, a markedly increased level of 2-undecanone was identified in the peritoneal fluid of P. aeruginosa -infected mice. 2-Undecanone elicited the activation of neutrophils in a G ai -phospholipase C pathway. However, 2-undecanone strongly inhibited responses to lipopolysaccharide and bactericidal activity of neutrophils against P. aeruginosa by inducing apoptosis. Our results demonstrate that 2-undecanone from P. aeruginosa limits the innate defense activity of neutrophils, suggesting that the production of inhibitory metabolites is a strategy of P. aeruginosa for escaping the host immune system.