Targeting the IL-20/IL-22 balance to restore pulmonary, intestinal and metabolic homeostasis after cigarette smoking and unhealthy diet – TheraSCUD2022

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.