To regulate inflammatory response, the host produces two main families of inflammatory mediators that are the cytokines and the oxylipins. These mediators act in concert to initiate the cardinal signs of inflammation and orchestrate its resolution. However, in clinics or in research, oxylipins are largely overlooked and the inflammatory response remains mostly studied only in the context of cytokine production. This considerably underestimates the complexity of the inflammatory response. Consequently, we still have a poor understanding of the mechanisms of dysregulated inflammation and the management of many ICU-related disorders such as the severe complications of COVID-19 disease remains mostly supportive. We hypothesize that the assessing capacity of the host to produce oxylipins in response to an immune insult could provide a potential new tool to better understand and assess dysregulated inflammation and patient heterogeneity. Using highly standardized immunophenotyping tools and a well-defined healthy donor cohort, we will first characterize the healthy oxylipin response and how it is co-regulated in parallel to cytokine responses. We will then study COVID-19 as a proof of concept disease to test our hypothesis. VARIANCE aims at improving the understanding and clinical management of dysregulated inflammation and associated complications. Our investigations will be based on the production of oxylipins by stimulated whole blood (WB) cells used as a proxy to assess host immune responsiveness. The VARIANCE project involves 3 partners (INRAE-UNH; Institut Pasteur-CB UTechS and Institut Pasteur-Translational Immunologie) who gathers complementary and interdisciplinary expertise and skills in biology & biochemistry of oxylipins, immunology & variability of the immune response, cell biology, MS-based lipidomics, epidemiology and biostatistics. It also has outstanding resources including cutting-edge equipments and unique biocollections and data warehouse from three clinical studies (i.e. the Milieu Interieur population study, St James Covid-19 Bioresources and the RADIPEM studies).

One of the most prominent features of the cellular stress response, is the phosphorylation of the alpha subunit of the eukaryotic translation initiation factor 2 (eIF2-a). This phosphorylation impacts many functional compartments of the cell, in a response known as the integrated stress response (ISR). The research consortium assembled for this project has a great expertise in the stress pathways involved in eIF2-a phosphorylation. Each laboratory has demonstrated individually the importance of several branches of the ISR for the control of eIF2-a phosphorylation during studies as diverse as the impact of anticancer agents on the immunogenicity of tumors, the production of cytokines during the detection of pathogens by innate immune cells (Clavarino et al. in revision) or the ability of mammalian cells to respond to amino acids starvation. Although these results were obtained independently, they all intersect and raise important questions on the role of the ISR and the regulation of eIF2-a phosphorylation in the initiation of the immune response, as well as tumorogenesis. As a result, our collective aim is to define the molecular characteristics and specificities of the different ISR(s) induced in response to various chemotherapeutic agents,microbial stimuli or physiological disorders. In particular, we need to establish how autophagy, translation and the ISR are co-regulated in response to stress and how these important biochemical functions can be manipulated, through the identification of novel molecular targets. We will further explore the importance of the ISR both during inflammation and tumor development/treatment by studying the negative feed-back mechanism preventing cell death during stress. The dephosphorylation of eIF2-a though the induced expression of Ppp1r15a (GADD34), which forms a functional complex with protein phosphatase 1 (PP1) and thereby restore protein synthesis, will be at the center of this study. In particular the use of GADD34 specific inhibitors that competitively disrupt the interaction between PP1 and GADD34 will be tested in different experimental conditions and mouse disease models. Each of the teams of the consortium has developed a range of technical expertise and experimental tools, which will be of great importance for the study of the biochemical pathways structured around eIF2-a phosphorylation in vitro and in vivo.

To achieve a more sustainable future for all, there is growing interest in the use of plant-based diets for human nutrition. Recent findings suggest that replacing animal protein-rich foods with plant-based protein sources could be associated with health benefits and successful aging. Aging is associated with a decline in muscle mass and function that leading to adverse health outcomes and poor quality of life. Thus, the quality of dietary protein has a major role in maintaining muscle health in the elderly. Although plant-based diets could have health benefits for elderly, plant proteins are less anabolic than animal-derived proteins. However, plant proteins quality could be improved by combining different plant sources, as legume and cereals, to achieve a more favorable amino acid profile. Moreover, not only protein but also plant food matrix could contribute to maintain muscle health in seniors as dietary fibres or polyunsaturated fatty acids. However, effects of plant-based diet on muscle metabolism in the elderly remain to be studied and clinical studies are needed. The main objective of the present project is to determine how increase in the share of plant foods in the diet impacts skeletal muscle mass, function and protein metabolism, as well as the main metabolic markers in elderly. A clinical study will be conducted to compare the effects of diets containing different proportions of plant foods on skeletal muscle mass and function and protein metabolism in healthy older men and women. Subsequently, omics analyses will identify molecular mechanisms and potential muscle biomarkers that could reflect metabolic changes of skeletal muscle associated to plant-based diet. Thus, our MYOVEG project will provide information about the consequences of a switch towards more plant foods on muscle health in elderly and will participate to recommendations for maintenance of muscle and global health in older men and women.

Cigarette smoking and unhealthy diet (SCUD) are major behavioral risk factors that contribute to the alarming rise in non-communicable inflammatory diseases. Cigarette smoking is often associated with unhealthy patterns of nutrient intake thus increasing the risk of developing metabolic disorders notably through its impact on intestinal homeostasis. Importantly, obesity and smoking promote inflammatory disorders associated with gut microbiota alteration (referred to as dysbiosis). Among the factors playing a key role in the association between inflammation and dysbiosis are cytokines such as IL-22 and IL-20 subfamily members (IL-19, IL-20, IL-24). IL-22 signals through a IL-22RA1/IL-10RB heterodimeric receptor whereas the IL-20 signaling is dependent of the IL-20RB chain. Although these cytokines share common properties particularly on epithelia, some recent reports and our preliminary datas showed a functional antagonism between IL-22 and the IL-20-related cytokines, particularly during cigarette smoke exposure. Indeed, we showed that the increased susceptibility to respiratory infection resulting from CS exposure is associated with a defect in IL-22 production and is abrogated by treatment with anti-IL-20RB antibodies. To study the consequences of SCUD exposure, we have developed an experimental murine model in which we reproduce the main metabolic and inflammatory features of SCUD exposure found in humans. In this model, we will test the hypothesis that an imbalance between IL-20 and IL-22 is responsible for the inflammatory disorders associated with SCUD through the induction of gut and/or lung microbial dysbiosis. We propose that targeting of the IL-20/IL-22 balance may represent a new preventive/therapeutic approach to prevent the pulmonary, intestinal and metabolic disorders associated with SCUD. For this, TheraSCUD2022 project integrates 3 workpackages (WP) aiming, by multidisciplinary approaches: 1) to describe the role of the IL-20 cytokine subfamily members in the alterations resulting from SCUD; 2) to characterize the IL-20/IL-22 signaling pathways that are involved in these health consequences, by using appropriate deficient (KO) mice and recombinant cytokines; 3) to propose novel therapeutic approaches controlling the IL-20/IL-22 dysbalance and limiting the SCUD-related disorders. For this, both blocking anti-IL-20RB and neutralizing anti-IL-20 antibodies will be used for the treatment of mice exposed to SCUD. By addressing the association between environmental stress and non-communicable chronic inflammatory diseases, TheraSCUD2022 will decipher the mechanisms leading to the development of these major life-threatening pathologies. Our data mining strategies will allow the identification of the factors involved in the combined effects of SCUD (particularly among the IL-22/ IL-20 pathways) and should define biological markers for these diseases. Namely, we will decipher the interplay between IL-20/IL-22 cytokines, microbiota, metabolism and their consequences on SCUD-induced physiopathology. By proposing antibodies blocking the IL-20 pathway, we shall offer new therapeutic interventional strategies in diseases associated with SCUD by restoring microbiota and immune homeostasis. In summary, our project is dedicated to greatly improve our knowledge about the consequences of SCUD exposure, the physiopathological mechanisms involved, to define markers for the incoming or the progression of SCUD-related diseases and to propose therapeutic strategy. Altogether our project well respond to the Axis 3 of the challenge 4 and also concerns some aspects of the axis 6 (microbiota) and 13 (One Health). By its originality and its potential impact for socio-economically disadvantaged populations, TheraSCUD2022 should lead to major scientific, economic and social outcomes.