bioRxiv Science⌕ Search

Biology subjects

Turtoi, E.

Publications and source records attributed to Turtoi, E..

3 recordsLinked to original sources
bioRxiv2023

Tuft cell-derived acetylcholine is an effector of type 2 immunity and directly targets helminth parasites in the gut lumen

Upon parasitic helminth infection, activated intestinal tuft cells secrete IL-25, which initiates a type 2 immune response during which lamina propria ILC2s produce IL-13. This causes epithelial remodelling, including tuft cell hyperplasia with an unknown function. We describe a novel cholinergic effector function of tuft cells, which we show are the only epithelial cells expressing Choline Acetyltransferase (ChAT). During parasite infections, mice with epithelial-specific deletion of ChAT have increased worm burden and faecal egg counts although they are able to mount a comparable type 2 immune response. Mechanistically, IL-13-amplified tuft cells release acetylcholine (ACh) into the gut lumen. We demonstrate a direct effect of ACh on worms, reducing their viability and fecundity via helminth muscarinic ACh receptors, with effects promoted by inhibition of acetylcholinesterase, an helminth-secreted enzyme. Thus, tuft cells are sentinels in naive mice, and their amplification upon helminth infections serves an additional type 2 immune response effector function.

immunology↗
bioRxiv2020

Control of polyunsaturated fatty acids desaturation by Sting regulates inflammatory responses

Inflammatory disorders are major health issues in which immune function and metabolic homeostasis are concertedly altered. Yet, the molecular mechanisms coordinating innate and metabolic pathways in homeostatic conditions are poorly understood. Here, we unveil a negative regulatory feedback loop involving the Stimulator of interferon genes (Sting) and the Fatty acid desaturase 2 (Fads2). At steady state, Sting regulates FA metabolism by repressing the activity of the Fads2 enzyme responsible for the desaturation of polyunsaturated FAs (PUFAs). Importantly, Sting activation increased Fads2 activity, while antagonizing Fads2 enhanced Sting activation, promoting the establishment of an anti-viral state. Remarkably, the cross-regulation between Sting and Fads2 is mediated by the cyclic GMP-AMP (cGAMP) Sting agonist and PUFAs. Indeed, we found that PUFAs inhibit Sting activation, while Sting agonists bind Fads2. Thus, our study identifies Sting as a master regulator of FA metabolism, and PUFAs as modulators of Sting-dependent inflammation. The interplay between Fads2 and Sting determines the fine-tuning of inflammatory responses, but comes at the expense of metabolic alterations, which are critical to consider in human pathologies associated with aberrant Sting activation.

immunology↗
bioRxiv2019

The molecular landscape and microenvironment of salivary duct carcinoma reveal new therapeutic opportunities

Salivary duct carcinoma (SDC) is a rare and aggressive salivary gland cancer subtype with poor prognosis. The mutational landscape of SDC has been described rather exhaustively; yet, with respect to functional genomics and tumor microenvironment, little is known. In this study, transcriptomics and proteomics were combined to obtain the first characterization of the pathways deregulated in SDC. The data revealed the importance of Notch, TGB-{beta}, and interferon-{gamma} signaling. After associating computational biology, immunohistochemistry, multiplexed immunofluorescence, and digital imaging the first steps towards charting the cellular network within the microenvironment was initiated. According to immune infiltrate, two well-defined groups of tumors were observed, novel SDC immune checkpoints were discovered, and the key role played by macrophages and potentially NK cells in immunosuppression was shown. Furthermore, a clear trend between recurrence-free survival and M2 macrophage abundance was apparent. Independently, a measure of desmoplastic stromal reaction as determined by -SMA abundance, was also shown. Altogether, these many findings open new perspectives for understanding and treating SDC. Before applying an immunotherapy, classical patient stratification according to immune infiltrate should be taken into account. Moreover, the microenvironment offers new potential targets including macrophages or NK cells, or even fibroblasts or hyaluronic acid. Related therapies that have been developed against, e.g., pancreatic tumors could inspire equivalent therapy for SDC.\n\nAdditional informationO_LIFinancial support: MA (1 grant, GIRCI SOOM API-K 2016-811-DRC-AC), JC (2 grants, Fondation ARC PJA 20141201975, Labex EpiGenMed ANR 10-LABX-0012), AT (2 grants, Gunma University GIAR Research Program for Omics-Based Medical Science, Labex MabImprove ANR 10-LABX-0053 starting grant), ET (1 grant, SIRIC Montpellier Cancer Grant INCa_Inserm_DGOS_12553).\nC_LIO_LINo conflict of interest\nC_LIO_LI5408 words, 1 table, and 4 figures\nC_LI\n\nStatement of translational relevanceBased on the presence or absence of an immune infiltrate, two groups of SDC were identified. These have the potential to provide a rationale for therapy and clinical trial enrolment. Two novel immune checkpoints that could be targeted were also identified; namely, CTLA-4/CD86 and TIM-3/galectin-9. Both showed the important contribution that macrophages and NK cells have in immunosuppression. Treatments that induce reprogramming or elimination of these cells could be considered. Moreover, the importance of the desmoplastic stroma was stressed. The stroma acts as a physical barrier against therapy suggesting that strategies developed against pancreatic tumors could inspire SDC treatments. For SDC devoid of immune infiltrate, components of the stroma including fibroblasts or hyaluronic acid could be targeted, e.g., in combination with drugs against immune checkpoints or mutated genes. Finally, evidence that Notch and TGF-{beta} signaling are prevalent in SDC was obtained. This translates into additional therapeutic options.

cancer biology↗