Investigation of exosomal metabolomic profile in sarcoidosis and their functional effects in on immune cells

Bakgrund: Sarcoidosis is a systemic granulomatus disease with unclear causes. Genetic and environmental factors are key determinants of disease initiation as well as disease pathogenesis which has different clinical phenotypes. Currently there is no specific identified biomarker for efficient diagnosis and no treatment strategy targeting the pathogenic pathways.

Recent evidence show that altered lipid metabolism, changes in cellular energetics and glycolytic dysregulation affect immune responses as well as lung cellular integrity. This suggest that changes in metabolic pathways might play a role in disease pathogenesis. Exosomes are natural nano-vesicles secreted from most cells packed with biological cargo such as lipids, nucleic acids and metabolites.

They have been found to alter metabolic and immune responses in cells. We discovered that sarcoidosis patients have exosomes in their bronchoalveolar lavage fluid (BALF) with inflammatory activity and enriched with inflammation-associated proteins such as leukotriene forming enzymes.

Målsättning: There is a number of evidences showing that metabolic changes might be the key factors behind the persistent inflammation in sarcoidosis and the unpredictable disease course. Our discoveries show that exosomes have a significant inflammatory role in sarcoidosis. Here, we want to characterize the metabolic profile of exosomes present in BALF and plasma samples from sarcoidosis patients.

Furthermore, we want to investigate whether exosomes induce inflammation via altering metabolic pathways in different immune cells.

Arbetsplan: We will first characterize the full metabolomics profile of exosomes in BALF and plasma samples from sarcoidosis patients. Any difference detected between sarcoidosis and control samples will be used for hypothesis generation and for further detailed investigation of the exosomal metabolites. We will test if exosomes stimulate immune cells due to their metabolite cargo.

Lastly, we will validate if sarcoidosis exosomes cause changes in the metabolic pathways of different immune cells by in vitro assays.

Betydelse: Investigating changes in exosomal metabolome from patients’ body fluids like BALF and plasma can provide clinical information on disease stage and response to treatment. In addition to providing novel disease biomarkers, metabolomics can also elucidate fundamental exosome induced cellular mechanism in sarcoidosis and contribute to the development of new therapeutic strategies.