To establish a valid humanized model-system to screen for adipocyte immuno-metabolic response to plasma of ALS patients.
10-20% of ALS patients will develop a rapidly progressing disease, emphasizing the urgency to identify unique molecular signatures linked to these aggressive variants. Mounting evidence suggest key roles of a chronic and systemic immune response dysregulation in ALS pathobiology. Recently, we observed a decrease in protein expression of most immune mediators, notably the metabolic sensor leptin, in the plasma of sporadic ALS patients. Furthermore, we identified a distinct immuno-metabolic molecular signature among fast progressors characterized by elevated soluble tumor necrosis factor receptor II (sTNF-RII) and further reduced leptin levels.
Human primary subcutaneous pre-adipocytes were differentiated into adipocyte. Mature cells were harvested after a 12-hour treatment with one of the following: lipopolysaccharide (LPS), plasma from one of 65 ALS patients (46 slow and 19 fast progressors) or plasma from one of 44 healthy controls. Samples were also treated with or without sTNF-RII blocking antibody. 62 immuno-metabolic related molecules were quantified in the cell media.
Controlled immune challenge using LPS decreased the secretion of 20 immuno-metabolic mediators in the adipocyte media, notably leptin, in a dose-response manner.
Exposure to male sALS patient plasma significantly decreased secretion of 27 immuno-metabolic mediators in the adipocyte media, and this more strongly (notably leptin) or solely when exposed to fast-progressing patient plasma for 13 of these markers.
Blocking sTNF-RII in the plasma of fast-progressing patients restored partially leptin secretion in adipocytes conditioned by this patient subset’s plasma.
This work supports the hypothesis that immune dysregulation in ALS patient plasma results in alteration of human adipocyte response, notably a decreased leptin secretion. This study gives insight into the relationship between sTNF-RII and leptin, underscoring the potential of these two markers’ potential as molecular predictors and therapeutic targets for fast-progressing ALS.