Olivier NF Cexus

Dr Olivier NF Cexus


Principal Investigator (Res.B) in Immunology & Metabolism
PhD
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Academic and research departments

Section of Immunology, School of Biosciences.

Publications

Dong Park, Tatsuya Kozaki, Satish Tiwari, Marco Moreira, Ahad Khalilnezhad, Federico Torta, Nicolas Olivié, Chung Thiam, Oniko Liani, Aymeric Silvin, Wint Phoo, Liang Gao, Alexander Triebl, Wai Tham, Leticia Gonçalves, Wan Kong, Sethi Raman, Xiao Zhang, Garett Dunsmore, Charles Dutertre, Salanne Lee, Jia Ong, Akhila Balachander, Shabnam Khalilnezhad, Josephine Lum, Kaibo Duan, Ze Lim, Leonard Tan, Ivy Low, Kagistia Utami, Xin Yeo, Sylvaine Di Tommaso, Jean-William Dupuy, Balazs Varga, Ragnhildur Karadottir, Mufeeda Madathummal, Isabelle Bonne, Benoit Malleret, Zainab Binte, Ngan Da, Yingrou Tan, Wei Wong, Jinqiu Zhang, Jinmiao Chen, Radoslaw Sobota, Shanshan Howland, Lai Ng, Frédéric Saltel, David Castel, Jacques Grill, Veronique Minard, Salvatore Albani, Jerry Chan, Morgane Thion, Sang Jung, Markus Wenk, Mahmoud Pouladi, Claudia Pasqualini, Veronique Angeli, Olivier Cexus, Florent Ginhoux (2023)iPS-cell-derived microglia promote brain organoid maturation via cholesterol transfer, In: Nature (London)623(7986)pp. 397-5 Nature Publishing Group

Microglia are specialized brain-resident macrophagesthat arise from primitive macrophages colonizing the embryonic brain1. Microglia contribute to multiple aspects of brain development, but their precise roles in the early human brain remain poorly understood owing to limited access to relevant tissues2-6. The generation of brain organoids from human induced pluripotent stem cells recapitulates some key features of human embryonic brain development7-10. However, current approaches do not incorporate microglia or address their role in organoid maturation11-21. Here we generated microglia-sufficient brain organoids by coculturing brain organoids with primitive-like macrophages generated from the same human induced pluripotent stem cells (iMac)22, in organoid cocultures, iMac differentiated into cells with microglia-like phenotypes and functions (iMicro) and modulated neuronal progenitor cell (NPC) differentiation, limiting NPC proliferation and promoting axonogenesis. Mechanistically, iMicro contained high levels of PL1N2+ lipid droplets that exported cholesterol and its esters, which were taken up by NPCs in the organoids. We also detected PL1N2+ lipid droplet-loaded microglia in mouse and human embryonic brains. Overall, our approach substantially advances current human brain organoid approaches by incorporating microglial cells, as illustrated by the discovery of a key pathway of lipid-mediated crosstalk between microglia and NPCs that leadsto improved neurogenesis.

Olivier Nicolas Felix Cexus, Delphine Labrousse, Alessandro Luciani, Tim Elliott, Luigi Maiuri, Sonia Quaratino, Olivier Nicholas Felix Cexus (2009)Novel role of tissue transglutaminase (TG2) in chronic inflammatory diseases (48.12), In: The Journal of immunology (1950)182(1_Supplement)pp. 48-48.12

Abstract Tissue transglutaminase (TG2) has a critical role in the pathogenesis of chronic inflammatory diseases. We have previously described the key role of TG2 in cystic fibrosis (CF), a genetic disease characterised by chronic lung infections and inflammation. In CF, mutation on the CFTR gene results in an increased TG2 expression and activity leading to functional sequestration of the anti-inflammatory PPARγ and increase of inflammation. Here we tested whether in vivo inhibition of TG2 can reverse inflammation in chronic inflammatory diseases. To assess the importance of TG2, we injected cystamine, a potent TG2 inhibitor, in a transgenic mouse model of CF and in the TAZ10 transgenic mice that spontaneously develop autoimmune thyroiditis. Intraperitoneal administration of cystamine had a significant impact on the lung epithelium in the CF model, where it decreased TG expression and activity. The treatment was also able to dampen all the classic inflammatory parameters as well as restoring normal cellular levels of functional PPARγ. Interestingly, cystamine injections could also block inflammation in the TAZ10 TCR transgenic mouse model, highlighting the pivotal role of TG2 in generating inflammation in two very different pathologies. This work underlines the critical role of TG2 in inflammation and provides new opportunities to develop therapeutic strategies for sufferers of chronic inflammatory diseases.

Holly-May Lewis, Priyanka Gupta, Kyle DG Saunders, Shazneil Briones, Johanna Von Gerichten, Paul A Townsend, Eirini Velliou, Dany Beste, Olivier Cexus, Roger Paul Webb, Melanie Jane Bailey (2023)Nanocapillary sampling coupled to liquid chromatography mass spectrometry delivers single cell drug measurement and lipid fingerprints, In: Analyst148(5)pp. 1041-1049 Royal Society of Chemistry

This work describes the development of a new approach to measure drug levels and lipid fingerprints in single living mammalian cells. Nanocapillary sampling is an approach that enables the selection and isolation of single living cells under microscope observation. Here, live single cell nanocapillary sampling is coupled to liquid chromatography for the first time. This allows molecular species to be separated prior to ionisation and improves measurement precision of drug analytes. The efficiency of transferring analytes from the sampling capillary into a vial was optimised in this work. The analysis was carried out using standard flow liquid chromatography coupled to widely available mass spectrometry instrumentation, highlighting opportunities for widespread adoption. The method was applied to 30 living cells, revealing cell-to-cell heterogeneity in the uptake of different antibiotics. Using this system, we detected 14-158 lipid features per single cell, revealing the association between bedaquiline uptake and lipid fingerprints.

Ester Badami, Olivier Cexus, Marco Londei, Sonia Quaratino, Olivier Nicholas Felix Cexus (2006)OR.44. Naturally Arising Antigen-Specific Cd4+Cd25+ Regulatory T‐Cells Fail to Protect from Spontaneous Autoimmunity, In: Clinical immunology (Orlando, Fla.)119pp. S20-S20 Elsevier Inc
Ester Badami, Olivier Cexus, Marco Londei, Sonia Quaratino, Olivier Nicholas Felix Cexus (2006)F.89. The Immune Regulatory Function of Double Negative T-Cells in Autoimmunity, In: Clinical immunology (Orlando, Fla.)119pp. S82-S82 Elsevier Inc
Aymeric Silvin, Stefan Uderhardt, Cecile Piot, Sandro Da Mesquita, Katharine Yang, Laufey Geirsdottir, Kevin Mulder, David Eyal, Zhaoyuan Liu, Cecile Bridlance, Morgane Sonia Thion, Xiao Meng Zhang, Wan Ting Kong, Marc Deloger, Vasco Fontes, Assaf Weiner, Rachel Ee, Regine Dress, Jing Wen Hang, Akhila Balachander, Svetoslav Chakarov, Benoit Malleret, Garett Dunsmore, Olivier Cexus, Jinmiao Chen, Sonia Garel, Charles Antoine Dutertre, Ido Amit, Jonathan Kipnis, Florent Ginhoux, Olivier Nicholas Felix Cexus (2022)Dual ontogeny of disease-associated microglia and disease inflammatory macrophages in aging and neurodegeneration, In: Immunity (Cambridge, Mass.)55(8)pp. 1448-1465.e6 Elsevier Inc

Brain macrophage populations include parenchymal microglia, border-associated macrophages, and recruited monocyte-derived cells; together, they control brain development and homeostasis but are also implicated in aging pathogenesis and neurodegeneration. The phenotypes, localization, and functions of each population in different contexts have yet to be resolved. We generated a murine brain myeloid scRNA-seq integration to systematically delineate brain macrophage populations. We show that the previously identified disease-associated microglia (DAM) population detected in murine Alzheimer’s disease models actually comprises two ontogenetically and functionally distinct cell lineages: embryonically derived triggering receptor expressed on myeloid cells 2 (TREM2)-dependent DAM expressing a neuroprotective signature and monocyte-derived TREM2-expressing disease inflammatory macrophages (DIMs) accumulating in the brain during aging. These two distinct populations appear to also be conserved in the human brain. Herein, we generate an ontogeny-resolved model of brain myeloid cell heterogeneity in development, homeostasis, and disease and identify cellular targets for the treatment of neurodegeneration. [Display omitted] •M-Verse as a global cross-comparison of developing and adult murine brain macrophages•DAM correspond to a fetal-like reprogramming similar to Youth-Associated Microglia•DIMs appear during aging and increase in neurodegenerative diseases•DAM are embryonic derived, whereas DIMs are TREM2-independent monocyte derived Through 6 scRNA-seq brain dataset integration, the authors generated a myeloid map called M-Verse to delineate macrophage population heterogeneity. M-Verse revealed two distinct macrophage populations expressing published disease-associated microglia (DAM) signature: embryonically derived TREM2-dependent DAM and monocyte-derived TREM2-independent disease inflammatory macrophages (DIMs).

Alessandro Luciani, Valeria Rachela Villella, Angela Vasaturo, Ida Giardino, Massimo Pettoello-Mantovani, Stefano Guido, Olivier N Cexus, Nick Peake, Marco Londei, Sonia Quaratino, Luigi Maiuri (2010)Lysosomal accumulation of gliadin p31–43 peptide induces oxidative stress and tissue transglutaminase-mediated PPARγ downregulation in intestinal epithelial cells and coeliac mucosa, In: Gut59(3)pp. 311-319

BackgroundAn unresolved question in coeliac disease is to understand how some toxic gliadin peptides, in particular p31–43, can initiate an innate response and lead to tissue transglutaminase (TG2) upregulation in coeliac intestine and gliadin sensitive epithelial cell lines.AimWe addressed whether the epithelial uptake of p31–43 induces an intracellular pro-oxidative envoronment favouring TG2 activation and leading to the innate immune response.MethodsThe time course of intracellular delivery to lysosomes of p31–43, pα-2 or pα-9 gliadin peptides was analysed in T84 and Caco-2 epithelial cells. The effects of peptide challenge on oxidative stress, TG2 and peroxisome proliferator-activated receptor (PPAR)γ ubiquitination and p42/44–mitogen activated protein (MAP) kinase or tyrosine phosphorylation were investigated in cell lines and cultured coeliac disease biopsies with/without anti-oxidant treatment or TG2 gene silencing by immunoprecipitation, western blot, confocal microscopy and Fluorenscence Transfer Resonance Energy (FRET) analysis.ResultsAfter 24 h of challenge p31–43, but not pα-2 or pα-9, is still retained within LAMP1-positive perinuclear vesicles and leads to increased levels of reactive oxygen species (ROS) that inhibit TG2 ubiquitination and lead to increases of TG2 protein levels and activation. TG2 induces cross-linking, ubiquitination and proteasome degradation of PPARγ. Treatment with the antioxidant EUK-134 as well as TG2 gene silencing restored PPARγ levels and reversed all monitored signs of innate activation, as indicated by the dramatic reduction of tyrosine and p42/p44 phosphorylation.Conclusionp31–43 accumulation in lysosomes leads to epithelial activation via the ROS–TG2 axis. TG2 works as a rheostat of ubiquitination and proteasome degradation and drives inflammation via PPARγ downregulation.

Camille Bleriot, Emelie Barreby, Garett Dunsmore, Raphaelle Ballaire, Svetoslav Chakarov, Xenia Ficht, Giorgia De Simone, Francesco Andreata, Valeria Fumagalli, Wei Guo, Guochen Wan, Gregoire Gessain, Ahad Khalilnezhad, Xiao Meng Zhang, Nicholas Ang, Ping Chen, Cecilia Morgantini, Valerio Azzimato, Wan Ting Kong, Zhaoyuan Liu, Rhea Pai, Josephine Lum, Foo Shihui, Ivy Low, Connie Xu, Benoit Malleret, Muhammad Faris Mohd Kairi, Akhila Balachander, Olivier Cexus, Anis Larbi, Bernett Lee, Evan W. Newell, Lai Guan Ng, Wint Wint Phoo, Radoslaw M. Sobota, Ankur Sharma, Shanshan W. Howland, Jinmiao Chen, Marc Bajenoff, Laurent Yvan-Charvet, Nicolas Venteclef, Matteo Iannacone, Myriam Aouadi, Florent Ginhoux (2021)A subset of Kupffer cells regulates metabolism through the expression of CD36, In: Immunity (Cambridge, Mass.)54(9)pp. 2101-2116.e6 Elsevier

Tissue macrophages are immune cells whose phenotypes and functions are dictated by origin and niches. However, tissues are complex environments, and macrophage heterogeneity within the same organ has been overlooked so far. Here, we used high-dimensional approaches to characterize macrophage populations in the murine liver. We identified two distinct populations among embryonically derived Kupffer cells (KCs) sharing a core signature while differentially expressing numerous genes and proteins: a major CD206(lo)ESAM(-) population (KC1) and a minor CD206(hi)ESAM(+) population (KC2). KC2 expressed genes involved in metabolic processes, including fatty acid metabolism both in steady-state and in diet-induced obesity and hepatic steatosis. Functional characterization by depletion of KC2 or targeted silencing of the fatty acid transporter Cd36 highlighted a crucial contribution of KC2 in the liver oxidative stress associated with obesity. In summary, our study reveals that KCs are more heterogeneous than anticipated, notably describing a subpopulation wired with metabolic functions.

Anis Larbi, Olivier Cexus, Nabil Bosco (2018)Nutrition as a Tool to Reverse Immunosenescence?, In: S Chatterjee, W Jungraithmayr, D Bagchi (eds.), Immunity and Inflammation in Health and Disease: Emerging Roles of Nutraceuticals and Functional Foods in Immune Supportpp. 319-337 Elsevier
Paul A Townsend, Maria V Kozhevnikova, Olivier N F Cexus, Andrey A Zamyatnin, Jr, Surinder M Soond (2021)BH3-mimetics: recent developments in cancer therapy, In: Journal of experimental & clinical cancer research40(1)pp. 355-355

The hopeful outcomes from 30 years of research in BH3-mimetics have indeed served a number of solid paradigms for targeting intermediates from the apoptosis pathway in a variety of diseased states. Not only have such rational approaches in drug design yielded several key therapeutics, such outputs have also offered insights into the integrated mechanistic aspects of basic and clinical research at the genetics level for the future. In no other area of medical research have the effects of such work been felt, than in cancer research, through targeting the BAX-Bcl-2 protein-protein interactions. With these promising outputs in mind, several mimetics, and their potential therapeutic applications, have also been developed for several other pathological conditions, such as cardiovascular disease and tissue fibrosis, thus highlighting the universal importance of the intrinsic arm of the apoptosis pathway and its input to general tissue homeostasis. Considering such recent developments, and in a field that has generated so much scientific interest, we take stock of how the broadening area of BH3-mimetics has developed and diversified, with a focus on their uses in single and combined cancer treatment regimens and recently explored therapeutic delivery methods that may aid the development of future therapeutics of this nature.

Luigi Maiuri, Alessandro Luciani, Ida Giardino, Valeria Raia, Valeria R. Villella, Maria D'Apolito, Massimo Pettoello-Mantovani, Stefano Guido, Carolina Ciacci, Mariano Cimminoo, Olivier N. Cexus, Marco Londei, Sonia Quaratino (2008)Tissue transglutaminase activation modulates inflammation in cystic fibrosis via PPAR gamma down-regulation, In: The Journal of immunology (1950)180(11)pp. 7697-7705 Amer Assoc Immunologists

Cystic fibrosis (CF), the most common life-threatening inherited disease in Caucasians, is due to mutations in the CF transmembrane conductance regulator (CFTR) gene and is characterized by airways chronic inflammation and pulmonary infections. The inflammatory response is not secondary to the pulmonary infections. Indeed, several studies have shown an increased proinflammatory activity in the CF tissues, regardless of bacterial infections, because inflammation is similarly observed in CFTR-defective cell lines kept in sterile conditions. Despite recent studies that have indicated that CIF airway epithelial cells can spontaneously initiate the inflammatory cascade, we still do not have a clear insight of the molecular mechanisms involved in this increased inflammatory response. In this study, to understand these mechanisms, we investigated ex vivo cultures of nasal polyp mucosal explants of CF patients and controls, CFTR-defective IB3-1 bronchial epithelial cells, C38 isogenic CFTR corrected, and 16HBE normal bronchial epithelial cell lines. We have shown that a defective CFTR induces a remarkable up-regulation of tissue transglutarninase (TG2) in both tissues and cell lines. The increased TG2 activity leads to functional sequestration of the anti-inflammatory peroxisome proliferator-activated receptor y and increase of the classic parameters of inflammation, such as TNF-alpha, tyrosine phosphorylation, and MAPKs. Specific inhibition of TG2 was able to reinstate normal levels of peroxisome proliferator-activated receptor-gamma and dampen down inflammation both in CF tissues and CFTR-defective cells. Our results highlight an unpredicted central role of TG2 in the mechanistic pathway of CF inflammation, also opening a possible new wave of therapies for sufferers of chronic inflammatory diseases.

Ester Badami, Olivier N. F. Cexus, Sonia Quaratino (2019)Activation-induced cell death of self-reactive regulatory T cells drives autoimmunity, In: Proceedings of the National Academy of Sciences - PNAS116(52)pp. 26788-26797

Significance In the present study, we provide evidence of a cellular mechanism of breach of tolerance in an in vivo model of spontaneous autoimmune thyroiditis (AIT). We observe that self-antigen (Ag) specific T reg circulate in all lymphatic tissues except for the lymph nodes (LNs) draining the thyroid, which represents the site of inflammation. By contrast, cognate effector T cells accumulate in the draining LNs and thyroid. The absence of T reg unleashes cognate T eff , which promote tissue destruction. We demonstrate that the organ-restricted disappearance of T reg is driven by the self-Ag, aberrantly expressed in a highly inflammatory environment, by a mechanism of activation-induced cell death. Activation of self-reactive T cells is a major driver to autoimmunity and is suppressed by mechanisms of regulation. In a humanized model of autoimmune thyroiditis, we investigated the mechanism underlying break of tolerance. Here, we found that a human TCR specific for the self-antigen thyroid peroxidase (TPO) is positively selected in the thymus of RAG KO mice on both T effector (T eff ) and T regulatory (T reg ) CD4 + Foxp3 + cells. In vivo T eff are present in all immune organs, whereas the TPO-specific T reg are present in all lymphoid organs with the exception of the thyroid-draining lymph nodes. We suggest that the presence of TPO in the thyroid draining lymph nodes induces the activation of T eff and the depletion of T reg via activation-induced cell death (AICD). Our findings provide insights on the failure of the mechanisms of immune tolerance, with potential implications in designing immunotherapeutic strategies.

Anteneh Mehari Tizazu, Ma Shwe Zin Nyunt, Olivier Cexus, Koolarina Suku, Esther Mok, Chin Hui Xian, Joni Chong, Crystal Tan, Wilson How, Sandra Hubert, Emilie Combet, Tamas Fulop, Tze Pin Ng, Anis Larbi, Olivier Nicholas Felix Cexus (2019)Metformin Monotherapy Downregulates Diabetes-Associated Inflammatory Status and Impacts on Mortality, In: Frontiers in physiology10(MAY)pp. 572-572 Frontiers Media S.A

Aging is the main risk factor for developing diabetes and other age-related diseases. One of the most common features of age-related comorbidities is the presence of low-grade chronic inflammation. This is also the case of metabolic syndrome and diabetes. At the subclinical level, a pro-inflammatory phenotype was shown to be associated with Type-2 diabetes mellitus (T2DM). This low to mid-grade inflammation is also present in elderly individuals and has been termed inflammaging. Whether inflammation is a component of aging or exclusively associated with age-related diseases in not entirely known. We used clinical data and biological readouts in a group of individuals stratified by age, diabetes status and comorbidities to investigate this aspect. While aging is the main predisposing factor for several diseases there is a concomitant increased level of pro-inflammatory cytokines. DM patients show an increased level of sTNFRll, sICAM-1, and TIMP-1 when compared to Healthy, Non-DM and Pre-DM individuals. These inflammatory molecules are also associated with insulin resistance and metabolic syndrome in Non-DM and pre-DM individuals. We also show that metformin monotherapy was associated with significantly lower levels of inflammatory molecules, like TNFα, sTNFRI, and sTNFRII, when compared to other monotherapies. Longitudinal follow up indicates a higher proportion of death occurs in individuals taking other monotherapies compared to metformin monotherapy. Together our finding shows that chronic inflammation is present in healthy elderly individuals and exacerbated with diabetes patients. Likewise, metformin could help target age-related chronic inflammation in general, and reduce the predisposition to comorbidities and mortality.