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List of publications by EMBRN members

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Eur J Immunol. 2021 Feb;51(2):445-458. doi: 10.1002/eji.202048668. Epub 2020 Oct 14. Mast cells crosstalk with B cells in the gut and sustain IgA response in the inflamed intestine Viviana Valeri, Silvia Tonon, Shamila Vibhushan, Alessandro Gulino, Beatrice Belmonte, Monika Adori, Gunilla B Karlsson Hedestam, Gregory Gautier, Claudio Tripodo, Ulrich Blank, Francesca Mion, Carlo E M Pucillo PMID: 32920851 DOI: 10.1002/eji.202048668 B lymphocytes are among the cell types whose effector functions are modulated by mast cells (MCs). The B/MC crosstalk emerged in several pathological settings, notably the colon of inflammatory bowel disease (IBD) patients is a privileged site in which MCs and IgA+ cells physically interact. Herein, by inducing conditional depletion of MCs in red MC and basophil (RMB) mice, we show that MCs control B cell distribution in the gut and IgA serum levels. Moreover, in dextran sulfate sodium (DSS)-treated RMB mice, the presence of MCs is fundamental for the enlargement of the IgA+ population in the bowel and the increase of systemic IgA production. Since both conventional B-2 and peritoneal-derived B cells populate the intestine and communicate with MCs in physiological conditions and during inflammation, we further explored this interplay through the use of co-cultures. We show that MCs finely regulate different aspects of splenic B cell biology while peritoneal B cells are unresponsive to the supporting effects provided by MCs. Interestingly, peritoneal B cells induce a pro-inflammatory skewing in MCs, characterized by increased ST2 and TNF-α expression. Altogether, this study uncovers the versatility of the B/MC liaison and highlights key aspects for the resolution of intestinal inflammation. Keywords: IgA; cell-to-cell interplay; colitis; innate-like B cells; mast cells. undefined
Directional mast cell degranulation of tumor necrosis factor into blood vessels primes neutrophil extravasation Immunity 2021 Jan 15;S1074-7613(20)30545-8. doi: 10.1016/j.immuni.2020.12.017. Online ahead of print. Jan Dudeck, Johanna Kotrba, Roland Immler, Aaron Hoffmann, Martin Voss, Vasileia Ismini Alexaki, Lorena Morton, Stephan René Jahn, Konstantinos Katsoulis-Dimitriou, Simon Winzer, Georg Kollias, Thomas Fischer, Sergei A Nedospasov, Ildiko Rita Dunay, Triantafyllos Chavakis, Andreas J Müller, Burkhart Schraven, Markus Sperandio, Anne Dudeck PMID: 33484643 DOI: 10.1016/j.immuni.2020.12.017 Tissue resident mast cells (MCs) rapidly initiate neutrophil infiltration upon inflammatory insult, yet the molecular mechanism is still unknown. Here, we demonstrated that MC-derived tumor necrosis factor (TNF) was crucial for neutrophil extravasation to sites of contact hypersensitivity-induced skin inflammation by promoting intraluminal crawling. MC-derived TNF directly primed circulating neutrophils via TNF receptor-1 (TNFR1) while being dispensable for endothelial cell activation. The MC-derived TNF was infused into the bloodstream by directional degranulation of perivascular MCs that were part of the vascular unit with access to the vessel lumen. Consistently, intravenous administration of MC granules boosted neutrophil extravasation. Pronounced and rapid intravascular MC degranulation was also observed upon IgE crosslinking or LPs challenge indicating a universal MC potential. Consequently, the directional MC degranulation of pro-inflammatory mediators into the bloodstream may represent an important target for therapeutic approaches aimed at dampening cytokine storm syndromes or shock symptoms, or intentionally pushing immune defense.

Links:
Comment in Nature Reviews in Immunology (free access): www.nature.com/articles/s41577-021-00509-y
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AllergoOncology: ultra-low IgE, a potential novel biomarker in cancer-a Position Paper of the European Academy of Allergy and Clinical Immunology (EAACI). Ferastraoaru D, Bax HJ, Bergmann C, Capron M, Castells M, Dombrowicz D, Fiebiger E, Gould HJ, Hartmann K, Jappe U, Jordakieva G, Josephs DH, Levi-Schaffer F, Mahler V, Poli A, Rosenstreich D, Roth-Walter F, Shamji M, Steveling-Klein EH, Turner MC, Untersmayr E, Karagiannis SN, Jensen-Jarolim E. Clin Transl Allergy. 2020 Jul 17;10:32. doi: 10.1186/s13601-020-00335-w. eCollection 2020. PMID: 32695309 Free PMC article. Elevated serum IgE levels are associated with allergic disorders, parasitosis and specific immunologic abnormalities. In addition, pidemiological and mechanistic evidence indicates an association between IgE-mediated immune surveillance and protection from tumour growth. Intriguingly, recent studies reveal a correlation between IgE deficiency and increased malignancy risk. This is the first review discussing IgE levels and links to pathological conditions, with special focus on the potential clinical significance of ultra-low serum IgE levels and risk of malignancy. In this Position Paper we discuss: (a) the utility of measuring total IgE levels in the management of allergies, parasitosis, and immunodeficiencies, (b) factors that may influence serum IgE levels, (c) IgE as a marker of different disorders, and d) the relationship between ultra-low IgE levels and malignancy susceptibility. While elevated serum IgE is generally associated with allergic/atopic conditions, very low or absent IgE may hamper anti-tumour surveillance, indicating the importance of a balanced IgE-mediated immune function. Ultra-low IgE may prove to be an unexpected biomarker for cancer risk. Nevertheless, given the early stage of investigations conducted mostly in patients with diseases that influence IgE levels, in-depth mechanistic studies and stratification of malignancy risk based on associated demographic, immunological and clinical co-factors are warranted. undefined
A rational roadmap for SARS-CoV-2/COVID-19 pharmacotherapeutic research and development: IUPHAR Review 29. Alexander SPH, Armstrong JF, Davenport AP, Davies JA, Faccenda E, Harding SD, Levi-Schaffer F, Maguire JJ, Pawson AJ, Southan C, Spedding M. Br J Pharmacol. 2020 Nov;177(21):4942-4966. doi: 10.1111/bph.15094. Epub 2020 Jul 19. PMID: 32358833 In this review, we identify opportunities for drug discovery in the treatment of COVID-19 and in so doing, provide a rational roadmap whereby pharmacology and pharmacologists can mitigate against the global pandemic. We assess the scope for targetting key host and viral targets in the mid-term, by first screening these targets against drugs already licensed; an agenda for drug re-purposing, which should allow rapid translation to clinical trials. A simultaneous, multi-pronged approach using conventional drug discovery methodologies aimed at discovering novel chemical and biological means targetting a short-list of host and viral entities should extend the arsenal of anti-SARS-CoV-2 agents. This longer-term strategy would provide a deeper pool of drug choices for future-proofing against acquired drug resistance. Second, there will be further viral threats, which will inevitably evade existing vaccines. This will require a coherent therapeutic strategy which pharmacology and pharmacologists are best placed to provide. undefined
Fevipiprant, a DP2 receptor antagonist, inhibits eosinophil migration towards mast cells. Shamri R, Dubois G, Erpenbeck VJ, Mankuta D, Sandham DA, Levi-Schaffer F. Clin Exp Allergy. 2019 Feb;49(2):255-257. doi: 10.1111/cea.13304. Epub 2018 Nov 25. PMID: 30379368 Fevipiprant, a DP2 receptor antagonist, inhibits eosinophil migration towards mast cells undefined
A granulocytic signature identifies COVID-19 and its severity. Vitte J, Diallo AB, Boumaza A, Lopez A, Michel M, Allardet-Servent J, Mezouar S, Sereme Y, Busnel JM, Miloud T, Malergue F, Morange PE, Halfon P, Olive D, Leone M, Mege JL. J Infect Dis. 2020 Sep 17:jiaa591. doi: 10.1093/infdis/jiaa591. Online ahead of print. PMID: 32941618 Unsupervised mapping of leukocyte surface markers identified a granulocytic COVID-19 signature comprising eosinophil and basophil CRTH2 downregulation, increased counts of CD15+CD16+ neutrophils, and decreased granulocytic CD11b expression, while PDL1 checkpoint expression in basophils and eosinophils was associated with severity. undefined
Mezouar S, Vitte J, Gorvel L, Ben Amara A, Desnues B, Mege JL (2019) Mast Cell Cytonemes as a Defense Mechanism against Coxiella burnetii. MBio Apr 16;10(2). pii: e02669-18. PMID: 30992359 PMCID: PMC6469977 DOI: 10.1128/mBio.02669-18 Mast cells (MCs) are critical mediators of inflammation; however, their microbicidal activity against invading pathogens remains largely unknown. Here, we describe a nonpreviously reported antibacterial mechanism used by MCs against Coxiella burnetii, the agent of Q fever. We show that C. burnetii interaction with MCs does not result in bacterial uptake but rather induces the formation of extracellular actin filaments named cytonemes. MC cytonemes express cathelicidin and neutrophil elastase and mediate the capture and destruction of entrapped bacteria. We provide evidence that MC cytoneme formation and microbicidal activity are dependent on the cooperation of the scavenger receptor CD36 and Toll-like receptor 4. Taken together, our results suggest that MCs use an extracellular sophisticated mechanism of defense to eliminate intracellular pathogens, such as C. burnetii, before their entry into host cells.IMPORTANCE Mast cells (MCs) are found in tissues that are in close contact with external environment, such as skin, lungs, or intestinal mucosa but also in the placenta during pregnancy. If their role in mediating allergic conditions is established, several studies now highlight their importance during infection with extracellular pathogens. This study showed a new and effective antimicrobial mechanism of MCs against Coxiella burnetii, an intracellular bacterium whose infection during pregnancy is associated with abortion, preterm labor, and stillbirth. The data reveal that in response to C. burnetii, MCs release extracellular actin filaments that contain antimicrobial agents and are capable to trap and kill bacteria. We show that this mechanism is dependent on the cooperation of two membrane receptors, CD36 and Toll-like receptor 4, and may occur in the placenta during pregnancy by using ex vivo placental MCs. Overall, this study reports an unexpected role for MCs during infection with intracellular bacteria and suggests that MC response to C. burnetii infection is a protective defense mechanism during pregnancy. undefined
Mezouar S, Morel V, Leveille L, Resseguier N, Chartier C, Raoult D, Mege JL, Vitte J (2019) Progenitor mast cells and tryptase in Q fever. Comp Immunol Microbiol Infect Dis Jun;64:159-162. PMID: 31174692 DOI: 10.1016/j.cimid.2019.03.011 Q fever is an infectious disease due to Coxiella burnetii. Following a primary-infection, C. burnetii may persist in some patients, leading to endocarditis and vascular infections. Mast cells (MCs), known for their role in allergic diseases, innate immunity and cardiac function, are produced by bone marrow, circulate as progenitors in the bloodstream and reach tissues for their maturation and activation. The latter may be estimated by measuring serum tryptase levels. We wondered if MC progenitors and tryptase were affected in Q fever. We showed a decrease in MC progenitor count in Q fever patients whereas serum tryptase levels were increased. Taken together, our results show alterations of MC numbers and activity in Q fever patients, suggesting that MC are involved in Q fever pathophysiology. undefined
Mezouar, Soraya & Ben Amara, Amira & Vitte, Joana & Mege, Jean‐Louis. (2018). Isolation of Human Placental Mast Cells. Current Protocols in Cell Biology. 80. 10.1002/cpcb.52. Mast cells have been identified as resident cells of human placental tissue by immunohistological procedures, suggesting that they may play a role in pregnancy. undefined
Yu Y, Blokhuis BRJ, Diks MAP, Keshavarzian A, Garssen J and Redegeld FA (2018) Functional Inhibitory Siglec-6 Is Upregulated in Human Colorectal Cancer-Associated Mast Cells. Front. Immunol. 9:2138. doi: 10.3389/fimmu.2018.02138 Mast cells (MC) accumulate in colorectal cancer (CRC) and the relationship between MC density and cancer progression has been well recognized. undefined
Yingxin Yu, Bart Blokhuis, Yvonne Derks, Sangeeta Kumari, Johan Garssen & Frank Redegeld (2018) Human mast cells promote colon cancer growth via bidirectional crosstalk: studies in 2D and 3D coculture models, OncoImmunology, 7:11, e1504729, DOI: 10.1080/2162402X.2018.1504729 Chronic inflammation drives the development of colorectal cancer (CRC), where tumor-infiltrating immune cells interact with cancer cells in a dynamic crosstalk. undefined

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