Ass. MD TP9: Immunometabolic activities of drugs used in pemphigoid diseases

While the treatment of autoimmune diseases (such as, but not limited to, pemphigoid diseases) predominantly relies on the use of corticosteroids, immunosuppressive drugs and biologics, a variety of advances have been made in the past decades. Novel therapy strategies are being developed through the emerging field of immunometabolism, which aims to exploit the immune cell metabolism to modulate inflammatory responses1. The high energy demand of immune cells makes their metabolism central in all inflammatory processes. Nonetheless, the complex regulation and dependencies of immune cell activation and metabolic control require further investigation to effectively exploit key pathways for therapeutic treatments2.

Promising drug candidates have been tested in mouse models of pemphigoid diseases and were shown to be effective in other inflammatory diseases (i.e., psoriasis, multiple sclerosis)3–6. However, the underlying mechanisms are not fully uncovered yet. This is further complicated by the indications that the test substances interact with multiple target molecules in the cell, affecting distinct signaling and metabolic pathways.
This project is aimed to gauge the impact of metabolic modulators on inflammatory processes and to gain mechanistic insight into the cellular pathways affecting the disease activity. Macrophages demonstrate plasticity in both metabolism and immune function and are important players in many inflammatory processes. Application of the test substances is expected to alter cellular mechanisms in macrophages dependent on the stimulation-induced polarization pattern of these cells.
While the efficacy of the test substances has been established in human patients and in few mouse experiments, limited data is available on the inflammatory response on the cellular level and metabolic responses have not been evaluated.
The project will employ a macrophage cell line to assess metabolic phenotypes (i.e. glycolytic activity, respiration, redox potential) and immunological phenotypes (cell differentiation, cytokine production) under various stimulations in vitro. The work program will contain standard laboratory techniques (i.e., ELISA, fluorometric and chemiluminescence based plate assays, flow cytometry, qPCR), as well as glycolytic and respiratory flux analysis.
Initial experiments will aim to establish the response profiles for the test substances in the macrophage cell line. Upon identification of specific metabolic and immunological modulation patterns, additional experiments will aim verify the significance of the affected metabolic pathways, to identify synergistic effects and dose response effects between the test substances.

1.    O’Neill, L. A. J., Kishton, R. J. & Rathmell, J. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16, 553–565 (2016).
2.    Puleston, D. J., Villa, M. & Pearce, E. L. Ancillary Activity: Beyond Core Metabolism in Immune Cells. Cell Metab. 26, 131–141 (2017).
3.    Wozel, G. & Blasum, C. Dapsone in dermatology and beyond. Arch. Dermatol. Res. 306, 103–124 (2014).
4.    Brück, J., Dringen, R., Amasuno, A., Pau-Charles, I. & Ghoreschi, K. A review of the mechanisms of action of dimethylfumarate in the treatment of psoriasis. Exp. Dermatol. 27, 611–624 (2018).
5.    Wannick, M. et al. The Immunometabolomic Interface Receptor Hydroxycarboxylic Acid Receptor 2 Mediates the Therapeutic Effects of Dimethyl Fumarate in Autoantibody-Induced Skin Inflammation. Front. Immunol. 9, (2018).
6.    Chen, H. et al. Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate’s protective effect in EAE. J. Clin. Invest. 124, 2188–2192 (2014).