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Environmental modulators of the immune cell balance in health and disease

Periodic Reporting for period 4 - ENVIROIMMUNE (Environmental modulators of the immune cell balance in health and disease)

Reporting period: 2018-11-01 to 2020-07-31

The incidence of autoimmune diseases in developed societies is increasing at high rates, but the underlying cause for this phenomenon has not been elucidated yet. Since the genetic architect remains considerably stable, this increase is likely associated with changes in the environment. Autoimmunity is linked to an imbalance of pro-inflammatory Th17 cells and anti-inflammatory Foxp3+ regulatory T cells (Treg). However, little is known regarding environmental factors that influence the Th17/Treg balance. We recently discovered that a sodium-rich diet severely exacerbates experimental autoimmune encephalomyelitis (EAE) through an increased induction of pathogenic Th17 cells. Surprisingly, our preliminary data indicate that high-salt conditions also significantly impair Treg function, resembling a phenotype observed in several human autoimmune diseases. In addition, we have evidence that a high-salt diet affects the gut microbiota, implicating possible indirect effects on immune cells in vivo. Based on these findings we hypothesize that excess dietary salt represents an environmental risk factor for autoimmune diseases by modulating the Th17/Treg balance by several direct and indirect mechanisms. To address this hypothesis we will 1) examine the underlying mechanisms of high-salt induced Treg dysfunction and effects on the Treg/Th17 balance by molecular and functional analysis in vitro and compare it to known risk variants of human autoimmune diseases, and 2) define direct and indirect effects of excess dietary salt on the Th17/Treg balance and autoimmunity in vivo and explore potential novel pathways for targeted interventions. Thus, the proposed study will uncover the impact of a newly discovered environmental modulator of the immune cell balance and will ultimately pave the way for new approaches in therapy and prevention of autoimmune diseases.

In summary, the project was successful and we were able to gain new scientific insights how high-salt intake and changes in the ionic microenvironment directly and indirectly could impact the immune cell balance and models of disease. Thereby the action contributed to a better understanding how environmental factors may shape immune responses. Current major conclusions derived from the project are that a) the immune cell balance could be directly impacted by high-salt conditions through several layers of mechanism including alterations in immunometabolic states and b) that excess-salt intake could lead to shifts in the gut microbiota and thereby indirectly affects immune responses and models of disease, likely by altering abundance of bacterial derived immuno-modulatory metabolites.
The aim of the project ENVIROIMMUNE was to better understand the effects of environmental factors, like diet, on the immune cell balance and disease. Here we focused on high-salt intake and the ionic microenvironment in the context of autoimmunity. The balance between pro- and anti-inflammatory T cells is an important factor for disease development, and defects in the regulation of T cell responses are linked to disease. Based on our hypothesis that high-salt environments could impact the balance between pro- and anti-inflammatory T cell subsets and thereby may impact disease, we examined direct effects of high-salt conditions on human T cell subsets and further investigated how high-salt diets may indirectly affect the immune cell balance and disease.

In the framework of part 1 of the project we studied direct effects of high-salt conditions of human T cell subsets. By analysing global salt-induced molecular changes of in cell culture activated Th17 and Tregs and subsequent functional analysis by cell culture based assays and by using experimental models of disease, we were able to discover new pathways how changes in the ionic microenvironment affect T cell responses. A highly interesting aspect was the interference of salt with immunometabolism of T cells and subsequent impact on function, mimicking dysfunctional T cells found in patients with autoimmunity. These results are currently under further investigation to understand if it relates to human disease. Moreover, based on the huge set of generated data, analysis and exploitation of other pathways will be continued in the future.

In part 2 of the project we investigated potential indirect effects of high-salt intake on the immune cell balance, particularly concentrating on the gut microbiome. It is now well accepted that immune system and microbial communities residing in the gut are tightly interconnected and that changes in these gut microbial communities can have a major impact on the immune cell balance and disease. Together with our collaborators we discovered that high-salt intake indeed could impact gut microbial communities and thereby also indirectly modulate the immune cell balance and disease, as demonstrated in e.g. models of neuroinflammation. Based on collecting data from further experiments by modulating salt-intake we gained by now a clearer view on salt-induced changes on the gut microbiome and are currently analysing its impact on immune function and relation to disease in follow up studies.

Taken together the project contributed significantly to a better knowledge about the impact of environmental factors on the immune cell balance and disease. Our findings added novel insights into crucial mechanisms how sodium could modulate immune function by direct and indirect mechanism and thus may contribute to the future development of novel treatment and prevention strategies for diseases. Under the support of the ERC project several manuscripts were already published or submitted for publication and based on follow up studies we foresee further dissemination of data and findings based on the project.
With the project we have significantly contributed to key pieces of scientific evidence supporting major hypotheses of the proposed project ENVIROIMMUNE. As a spin-off project, resulting from generated data of the action, we further discovered that high-salt conditions could also inhibit tumor growth by enhancing anti-tumor immunity in model systems of disease. Here, particularly subtypes of myeloid cells, having a critical role in cancer and cancer immunotherapy seem to play an important role. Moreover, in the framework of the project we followed up some of the findings in other salt-sensitive immune cell types as well, like macrophages, also playing a critical role in many disease settings. The project further enabled us to develop and establish useful techniques and tools that would likely enhance research in follow up studies.