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2. Hyper-inflammatory profile and immunoparalysis in patients with severe Legionnaires' disease.

Author

Allam, Camille, Mouton, William, Testaert, Hugo, Ginevra, Christophe, Fessy, Noémie, Ibranosyan, Marine, Descours, Ghislaine, Beraud, Laetitia, Guillemot, Johann, Chapalain, Annelise, Albert-Vega, Chloé, Richard, Jean-Christophe, Argaud, Laurent, Friggeri, Arnaud, Labeye, Vanessa, Jamilloux, Yvan, Freymond, Nathalie, Venet, Fabienne, Lina, Gérard, and Doublet, Patricia

Subjects
LEGIONNAIRES' disease, SEPSIS, IMMUNITY, MULTIPLE organ failure
Abstract

Introduction: Severe Legionnaires' disease (LD) can lead to multi-organ failure or death in 10%-30% of patients. Although hyper-inflammation and immunoparalysis are well described in sepsis and are associated with high disease severity, little is known about the immune response in LD. This study aimed to evaluate the immune status of patients with LD and its association with disease severity. Methods: A total of 92 hospitalized LD patients were included; 19 plasmatic cytokines and pulmonary Legionella DNA load were measured in 84 patients on the day of inclusion (day 0, D0). Immune functional assays (IFAs) were performed from whole blood samples collected at D2 and stimulated with concanavalin A [conA, n = 19 patients and n = 21 healthy volunteers (HV)] or lipopolysaccharide (LPS, n = 14 patients and n = 9 HV). A total of 19 cytokines (conA stimulation) and TNF-α (LPS stimulation) were quantified from the supernatants. The Sequential Organ Failure Assessment (SOFA) severity score was recorded at D0 and the mechanical ventilation (MV) status was recorded at D0 and D8. Results: Among the 84 patients, a higher secretion of plasmatic MCP-1, MIP1-β, IL-6, IL-8, IFN-γ, TNF-α, and IL-17 was observed in the patients with D0 and D8 MV. Multiparametric analysis showed that these seven cytokines were positively associated with the SOFA score. Upon conA stimulation, LD patients had a lower secretion capacity for 16 of the 19 quantified cytokines and a higher release of IL-18 and MCP-1 compared to HV. IL-18 secretion was higher in D0 and D8 MV patients. TNF-α secretion, measured after ex vivo LPS stimulation, was significantly reduced in LD patients and was associated with D8 MV status. Discussion: The present findings describe a hyper-inflammatory phase at the initial phase of Legionella pneumonia that is more pronounced in patients with severe LD. These patients also present an immunoparalysis for a large number of cytokines, except IL-18 whose secretion is increased. An assessment of the immune response may be relevant to identify patients eligible for future innovative host-directed therapies. [ABSTRACT FROM AUTHOR]

Published
2023
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3. Chronic Exposure to Secondary Organic Aerosols Causes Lung Tissue Damage

Author

Déméautis, Tanguy, primary, Bouyssi, Alexandra, additional, Chapalain, Annelise, additional, Guillemot, Johann, additional, Doublet, Patricia, additional, Geloen, Alain, additional, George, Christian, additional, Menotti, Jean, additional, Glehen, Olivier, additional, Devouassoux, Gilles, additional, and Bentaher, Abderrazzak, additional

Published
2023
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9. TNF-α response in macrophages depends on clinical Legionella pneumophilaisolates genotypes

Author

Guillemot, Johann, Ginevra, Christophe, Allam, Camille, Kay, Elisabeth, Gilbert, Christophe, Doublet, Patricia, Jarraud, Sophie, and Chapalain, Annelise

Abstract

ABSTRACTLegionnaires’ Disease (LD) is a severe pneumonia mainly caused in Europe by Legionella pneumophilaserogroup 1 (Lp1). Sequence-based typing methods reveal that some sequence types (ST) are overrepresented in clinical samples such as ST1 and ST47, suggesting that some strains are more fit for infection than others. In the present study, a collection of 108 Lp1 clinical isolates were used to evaluate the strain-dependent immune responses from human macrophages. Clinical Lp1 isolates induced differential TNFα secretion from macrophages. ST1 isolates induced a significantly higher TNF-α secretion than non-ST1, whereas ST47 isolates induced a significantly lower TNF-α secretion than non-ST47 isolates. ST1 isolates induced a significantly higher cell death than ST47 isolates evaluated by lactate dehydrogenase activity (cytotoxicity) and caspase-3 activity (apoptosis). Treatment of macrophages with anti-TNF-α antibodies significantly reduced the cell death in macrophages infected with ST1 or ST47 strains. The TNF-α secretion was neither explained by a differential bacterial replication nor by the number or type (bystander or infected) of TNF-α producing cells following infection but by a differential response from macrophages. The Paris ST1 reference strain elicited a significantly higher TNF-αgene transcription and a higher induction of NF-κB signaling pathway than the Lorraine ST47 reference strain.Clinical Lp1 isolates induce a diverse immune response and cell death, which could be related to the genotype. The two predominant sequence-types ST1 and ST47 trigger opposite inflammatory response that could be related to the host susceptibility.

Published
2022
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10. Maternal prenatal undernutrition alters the response of POMC neurons to energy status variation in adult male rat offspring

Author

Breton, Christophe, Lukaszewski, Marie-Amelie, Risold, Pierre-Yves, Enache, Mihaela, Guillemot, Johann, Riviere, Guillaume, Delahaye, Fabien, Lesage, Jean, Dutriez-Casteloot, Isabelle, Laborie, Christine, and Vieau, Didier

Subjects
Fetal malnutrition -- Complications and side effects, Appetite -- Management, Hypothalamus -- Properties, Neurons -- Properties, Company business management, Biological sciences
Abstract

Epidemiological studies suggest that maternal undernutrition predisposes the offspring to development of energy balance metabolic pathologies in adulthood. Using a model of a prenatal maternal 70% food-restricted diet (FR30) in rats, we evaluated peripheral parameters involved in nutritional regulation, as well as the hypothalamic appetite-regulatory system, in nonfasted and 48-h-fasted adult offspring. Despite comparable glycemia in both groups, mild glucose intolerance, with a defect in glucose-induced insulin secretion, was observed in FR30 animals. They also exhibited hyperleptinemia, despite similar visible fat deposits. Using semiquantitative RT-PCR, we observed no basal difference of hypothalamic proopiomelanocortin (POMC) and neuropeptide Y (NPY) gene expression, but a decrease of the OB-Rb and an increase of insulin receptor mRNA levels, in FR30 animals. These animals also exhibited basal hypercorticosteronemia and a blunted increase of corticosterone in fasted compared with control animals. After fasting, FR30 animals showed no marked reduction of POMC mRNA levels or intensity of [beta]-endorphin-immunoreactive fiber projections. By contrast, NPY gene expression and immunoreactive fiber intensity increased. FR30 rats also displayed subtle alterations of food intake: body weight-related food intake was higher and light-dark phase rhythm and refeeding time course were modified after fasting. At rest, in the morning, hyperinsulinemia and a striking increase in the number of c-Fos-containing cells in the arcuate nucleus were observed. About 30% of the c-Fos-expressing cells were POMC neurons. Our data suggest that maternal undernutrition differently programs the long-term appetite-regulatory system of offspring, especially the response of POMC neurons to energy status and food intake rhythm. maternal undernutrition; appetite programming; hypothalamus; arcuate nucleus; feeding rhythm

Published
2009

23. Thrombin activation of protein C requires prior processing by a liver proprotein convertase.

Author

Essalmani, Rachid, primary, Susan-Resiga, Delia, additional, Guillemot, Johann, additional, Kim, Woojin, additional, Sachan, Vatsal, additional, Awan, Zuhier, additional, Chamberland, Ann, additional, Asselin, Marie-Claude, additional, Ly, Kévin, additional, Desjardins, Roxanne, additional, Day, Robert, additional, Prat, Annik, additional, and Seidah, Nabil G., additional

Published
2017
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26. Amyloid Precursor-like Protein 2 and Sortilin Do Not Regulate the PCSK9 Convertase-mediated Low Density Lipoprotein Receptor Degradation but Interact with Each Other

Author

Butkinaree, Chutikarn, primary, Canuel, Maryssa, additional, Essalmani, Rachid, additional, Poirier, Steve, additional, Benjannet, Suzanne, additional, Asselin, Marie-Claude, additional, Roubtsova, Anna, additional, Hamelin, Josée, additional, Marcinkiewicz, Jadwiga, additional, Chamberland, Ann, additional, Guillemot, Johann, additional, Mayer, Gaétan, additional, Sisodia, Sangram S., additional, Jacob, Yves, additional, Prat, Annik, additional, and Seidah, Nabil G., additional

Published
2015
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27. IGF2 Promotes Growth of Adrenocortical Carcinoma Cells, but Its Overexpression Does Not Modify Phenotypic and Molecular Features of Adrenocortical Carcinoma

Author

Guillaud-Bataille, Marine, primary, Ragazzon, Bruno, additional, de Reyniès, Aurélien, additional, Chevalier, Claire, additional, Francillard, Isabelle, additional, Barreau, Olivia, additional, Steunou, Virginie, additional, Guillemot, Johann, additional, Tissier, Frédérique, additional, Rizk-Rabin, Marthe, additional, René-Corail, Fernande, additional, Ghuzlan, Abir Al, additional, Assié, Guillaume, additional, Bertagna, Xavier, additional, Baudin, Eric, additional, Le Bouc, Yves, additional, Bertherat, Jérôme, additional, and Clauser, Eric, additional

Published
2014
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28. Circulating EM66 is a highly sensitive marker for the diagnosis and follow-up of pheochromocytoma

Author

Guillemot, Johann, Anouar, Youssef, Montero-Hadjadje, Maïté, Grouzmann, Eric, Grumolato, Luca, Roshmaninho-Salgado, Joana, Erie Turquier, Val, Duparc, Céline, Lefebvre, Hervé, Plouin, Pierre-François, Klein, Marc, Muresan, Mihaela, Chow, Billy, Vaudry, Hubert, Yon, Laurent, Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP 23), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Universidade de Coimbra [Coimbra], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre Hospitalier Universitaire de Nancy (CHU Nancy), and The University of Hong Kong (HKU)

Subjects
EM66, [SDV]Life Sciences [q-bio], chromogranins, pheochromo- cytoma, secretogranin II, neuroendocrine tumor, plasma marker
Abstract

International audience; We have previously demonstrated that measurement of tissue concentration of the novel secretogranin II-derived peptide EM66 may help to discriminate between benign and malignant pheo-chromocytomas. The aim of the present study was to characterize EM66 in plasma and urine of healthy volunteers and pheochromo-cytoma patients, in order to further evaluate the usefulness of this peptide as a circulating marker for the management of the tumors. HPLC analysis of plasma and urine samples demonstrated that the EM66-immunoreactive material coeluted with the recombinant peptide. In healthy volunteers, plasma and urinary EM66 levels were, respectively, 2.6 (1.9–3.7) ng/ml and 2.9 (1.9– 4.6) ng/ml. In patients with pheochromocytoma, plasma EM66 levels were 10-fold higher than those of healthy volunteers (26.9 (7.3– 44) ng/ml), and returned to normal values after removal of the tumor. In contrast, urinary EM66 levels were not significantly different from those of healthy volunteers (3.2 (2.2–3.9) ng/ml). Measurement of total or free plasma metanephrines and 24 hr uri-nary metanephrines in our series of patients revealed that these tests, taken separately, are less sensitive than the EM66 determination. Pheochromocytes in primary culture secreted high levels of EM66, suggesting that the chromaffin tumor was actually responsible for the increased plasma peptide concentrations in the patients. These data indicate that EM66 is secreted in the general circulation and that elevated plasma EM66 levels are correlated with the occurrence of pheochromocytoma. Thus, EM66 is a sensitive plasma marker that should be considered as a complementary tool in the management of pheochromocytoma. ' 2005 Wiley-Liss, Inc. Chromogranins (Cgs) constitute a family of acidic glycopro-teins encompassing chromogranin A (CgA), chromogranin B (CgB) and secretogranin II (SgII) that are widely distributed in neuroendocrine tissues where they are packaged in secretory granules. 1 The physiological role of these proteins is unclear but a number of potential biological functions have been postulated, including regulation of secretory granule formation and production of bioactive peptides through proteolytic processing. 2 It has been demonstrated that Cgs and Cgs-derived peptides are secreted together with hormones and neurotransmitters and can be detected in blood by radioimmuno assay (RIA) techniques. 3–5 This observation combined with their ubiquitous distribution in neuroendo-crine, endocrine and nervous tissues makes Cgs useful markers of secretion of normal and tumoral neuroendocrine cells. In particular , measurement of CgA levels in plasma can be used to diagnose or monitor the progression of neuroendocrine tumors. 6 The highest accuracy has been observed in tumors characterized by an intense secretory activity, although the specificity and sensitivity remain high also in nonfunctioning tumors. 7 However, CgA levels may also be elevated in patients with hyperplasia 3 and may therefore not be reliable for distinguishing neuroendocrine hyperplasia from adenoma or carcinoma. In addition, CgA measurement showed a low sensitivity in certain neuroendocrine tumors such as insulino-mas, pituitary adenomas and medullary thyroid carcinomas. 8,9 Thus, measurement of other Cgs or Cgs-derived peptides may be helpful for the diagnosis of different neuroendocrine tumors. It has been reported that plasma levels of GAWK and CCB, 2 CgB-derived peptides, are elevated in patients with pancreatic islet-cell tumors 10,11 or with bronchial tumors. 12 Similarly, enhanced plasma concentrations of the SgII-derived peptide secre-toneurin (SN) are associated with various endocrine tumors such as gastroenteropancreatic endocrine tumors or oat cell lung carci-nomas, and are also related to the progression of prostatic carcino-mas. 5,13 SgII is the precursor of 2 highly conserved peptides, i.e. SN and a 66-amino-acid C-terminal flanking peptide termed EM66. 14 Using specific polyclonal antibodies directed against recombinant EM66, we have previously shown the presence of EM66 in the rat pituitary and adrenal glands, 15 and in chromaffin cells of fetal and adult human adrenals. 16 We have recently demonstrated the occurrence of EM66 in human pheochromocytomas and found that low tissue concentrations of the peptide are associated with malignant differentiation of the tumor while benign pheochromocytomas contain significantly higher quantities of EM66, indicating that EM66 is a potential prognostic marker of chromaffin cell tumors. 17 Pheochromocytomas are usually benign but ~20% of these tumors are malignant, and to date the only evidence for malignancy is the occurrence of metastases, which are associated with a very poor survival rate. 18–20 The characterization of novel circulating markers is therefore crucial for the management of these tumors. As a further step in the evaluation of EM66 as a marker for the diagnosis and prognosis of pheochromocytoma, the aim of the present study was to characterize this peptide in plasma and urine, and to compare its concentrations between healthy volunteers and patients with pheochromocytoma. The ability of pheochromocytes in primary culture to release EM66 was also investigated.

Published
2006

31. Reply

Author

Guillemot, Johann, primary and Seidah, Nabil G., additional

Published
2013
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32. Granins and their derived peptides in normal and tumoral chromaffin tissue: Implications for the diagnosis and prognosis of pheochromocytoma

Author

Guérin, Marlène, primary, Guillemot, Johann, additional, Thouënnon, Erwan, additional, Pierre, Alice, additional, El-Yamani, Fatima-Zohra, additional, Montero-Hadjadje, Maité, additional, Dubessy, Christophe, additional, Magoul, Rabia, additional, Lihrmann, Isabelle, additional, Anouar, Youssef, additional, and Yon, Laurent, additional

Published
2010
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33. Expression of trophic amidated peptides and their receptors in benign and malignant pheochromocytomas: high expression of adrenomedullin RDC1 receptor and implication in tumoral cell survival

Author

Thouënnon, Erwan, primary, Pierre, Alice, additional, Tanguy, Yannick, additional, Guillemot, Johann, additional, Manecka, Destiny-Love, additional, Guérin, Marlène, additional, Ouafik, L'houcine, additional, Muresan, Mihaela, additional, Klein, Marc, additional, Bertherat, Jérôme, additional, Lefebvre, Hervé, additional, Plouin, Pierre-François, additional, Yon, Laurent, additional, and Anouar, Youssef, additional

Published
2010
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34. Metoclopramide stimulates catecholamine- and granin-derived peptide secretion from pheochromocytoma cells through activation of serotonin type 4 (5-HT4) receptors

Author

Guillemot, Johann, primary, Compagnon, Patricia, additional, Cartier, Dorthe, additional, Thouennon, Erwan, additional, Bastard, Christian, additional, Lihrmann, Isabelle, additional, Pichon, Perrine, additional, Thuillez, Christian, additional, Plouin, Pierre-François, additional, Bertherat, Jérôme, additional, Anouar, Youssef, additional, Kuhn, Jean-Marc, additional, Yon, Laurent, additional, and Lefebvre, Hervé, additional

Published
2009
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38. Circulating EM66 is a highly sensitive marker for the diagnosis and follow-up of pheochromocytoma

Author

Guillemot, Johann, primary, Anouar, Youssef, additional, Montero-Hadjadje, Maïté, additional, Grouzmann, Eric, additional, Grumolato, Luca, additional, Roshmaninho-Salgado, Joana, additional, Turquier, Valérie, additional, Duparc, Céline, additional, Lefebvre, Hervé, additional, Plouin, Pierre-François, additional, Klein, Marc, additional, Muresan, Mihaela, additional, Chow, Billy K.C., additional, Vaudry, Hubert, additional, and Yon, Laurent, additional

Published
2005
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41. Identification of the Secretogranin II-Derived Peptide EM66 in Pheochromocytomas as a Potential Marker for Discriminating BenignVersusMalignant Tumors

Author

Yon, Laurent, primary, Guillemot, Johann, additional, Montero-Hadjadje, Maite, additional, Grumolato, Luca, additional, Leprince, Jerome, additional, Lefebvre, Herve, additional, Contesse, Vincent, additional, Plouin, Pierre-François, additional, Vaudry, Hubert, additional, and Anouar, Youssef, additional

Published
2003
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42. The motif E X E XXX L in the cytosolic tail of the secretory human proprotein convertase PC7 regulates its trafficking and cleavage activity.

Author

Durand L, Duval S, Evagelidis A, Guillemot J, Dianati V, Sikorska E, Schu P, Day R, and Seidah NG

Subjects
Amino Acid Motifs genetics, Amino Acid Sequence genetics, Antigens, CD chemistry, Cell Membrane genetics, Cell Movement genetics, Cytosol chemistry, Endosomes genetics, HEK293 Cells, Humans, Receptors, Transferrin chemistry, Subtilisins chemistry, trans-Golgi Network genetics, Antigens, CD genetics, Cytosol metabolism, Protein Transport genetics, Receptors, Transferrin genetics, Subtilisins genetics, Transcription Factor AP-2 genetics
Abstract

Many secretory proteins are activated by cleavage at specific sites. The proprotein convertases (PCs) form a family of nine secretory subtilisin-like serine proteases, seven of which cleave at specific basic residues within the trans -Golgi network, granules, or at the cell surface/endosomes. The seventh member, PC7, is a type-I transmembrane (TM) protein with a 97-residue-long cytosolic tail (CT). PC7 sheds human transferrin receptor 1 (hTfR1) into soluble shTfR1 in endosomes. To better understand the physiological roles of PC7, here we focused on the relationship between the CT-regulated trafficking of PC7 and its ability to shed hTfR1. Deletion of the TMCT resulted in soluble PC7 and loss of its hTfR1 shedding activity. Extensive CT deletions and mutagenesis analyses helped us zoom in on three residues in the CT, namely Glu-719, Glu-721, and Leu-725, that are part of a novel motif, E X E XXX L 725 , critical for PC7 activity on hTfR1. NMR studies of two 14-mer peptides mimicking this region of the CT and its Ala variants revealed that the three exposed residues are on the same side of the molecule. This led to the identification of adaptor protein 2 (AP-2) as a protein that recognizes the E X E XXX L 725 motif, thus representing a potentially new regulator of PC7 trafficking and cleavage activity. Immunocytochemistry of the subcellular localization of PC7 and its Ala variants of Leu-725 and Glu-719 and Glu-721 revealed that Leu-725 enhances PC7 localization to early endosomes and that, together with Glu-719 and Glu-721, it increases the endosomal activity of PC7 on hTfR1., (© 2020 Durand et al.)

Published
2020
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44. Reply: To PMID 23390091.

Author

Guillemot J and Seidah NG

Subjects
Animals, Humans, Antigens, CD metabolism, Antimicrobial Cationic Peptides metabolism, Furin metabolism, Hepatocytes metabolism, Iron metabolism, Receptors, Transferrin metabolism, Subtilisins metabolism
Published
2013
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