The immunomodulatory potential of the arylmethylaminosteroid sc1o

Journal of Molecular Medicine https://doi.org/10.1007/s00109-020-02024-4 ORIGINAL ARTICLE The immunomodulatory potential of the arylmethylaminosteroid sc1o Leonard Blum 1,2 & Thomas Ulshöfer 1 & Marina Henke 1 & Reimar Krieg 3 & Isabell Berneburg 3 & Gerd Geisslinger 1,2 & Katja Becker 4 & Michael J. Parnham 1 & Susanne Schiffmann 1 Received: 11 May 2020 / Revised: 18 November 2020 / Accepted: 11 December 2020 # The Author(s) 2020 Abstract Developing resistance mechanisms of pathogens against established and frequently used drugs are a growing global health problem. Besides the development of novel drug candidates per se, new approaches to counteract resistance mechanisms are needed. Drug candidates that not only target the pathogens directly but also modify the host immune system might boost antiparasitic defence and facilitate clearance of pathogens. In this study, we investigated whether the novel anti-parasitic steroid compound 1o (sc1o), effective against the parasites Plasmodium falciparum and Schistosoma mansoni, might exhibit immunomodulatory properties. Our results reveal that 50 μM sc1o amplified the inflammatory potential of M1 macrophages and shifted M2 macrophages in a pro-inflammatory direction. Since M1 macrophages used predominantly glycolysis as an energy source, it is noteworthy that sc1o increased glycolysis and decreased oxidative phosphorylation in M2 macrophages. The effect of sc1o on the differentiation and activation of dendritic cells was ambiguous, since both pro- and anti-inflammatory markers were regulated. In conclusion, sc1o has several immunomodulatory effects that could possibly assist the immune system by counteracting the anti-inflammatory immune escape strategy of the parasite P. falciparum or by increasing pro-inflammatory mechanisms against pathogens, albeit at a higher concentration than that required for the anti-parasitic effect. Key messages • The anti-parasitic steroid compound 1o (sc1o) can modulate human immune cells. • Sc1o amplified the potential of M1 macrophages. • Sc1o shifts M2 macrophages to a M1 phenotype. • Dendritic cell differentiation and activation was ambiguously modulated. • Administration of sc1o could possibly assist the anti-parasitic defence. Keywords Steroid compound 1o . Macrophages . Dendritic cells . Immune modulation . Immune metabolism . Plasmodium falciparum * Susanne Schiffmann 1 Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Branch for Translational Medicine and Pharmacology (TMP), Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany 2 pharmazentrum frankfurt/ZAFES, Department of Clinical Pharmacology, Goethe-University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany 3 Department of Anatomy II, University Hospital Jena, Teichgraben 7, 07743 Jena, Germany 4 Biochemistry and Molecular Biology, Interdisciplinary Research Center, Justus-Liebig-University, Heinrich-Buff-Ring 26-32, 35392 Giessen, Germany Abbreviations ANOVA Analysis of variance ECAR Extracellular acidification rate FCS Foetal calf serum G M Granulocyte macrophage colony-stimulating CSF factor IFN Interferon IL Interleukin MdM Monocyte-derived macrophage MdDC Monocyte-derived dendritic cell OCR Oxygen consumption rate PBS Phosphate-buffered saline sc1o Steroid compound 1o J Mol Med Introduction Increasingly resistant pathogens are causing a global health problem with a variety of infectious diseases. The most important treatments for parasite-mediated diseases such as malaria (Plasmodium) and schistosomiasis (Schistosoma) are artemisinin combination therapies for malaria and praziquantel for schistosomiasis. The WHO reported 228 million cases of malaria worldwide in 2018 [1], while schistosomiasis affects approximately 200–250 million people, mostly in developing countries [2–4]. The frequent use of the available drugs increases the risk of resistance mechanisms. Reports relating to artemisinin-resistant parasites stress the urgent need for new therapeutic approaches [5, 6]. Besides resistance mechanisms against the drugs, Plasmodium further accentuates the challenge as it reduces the defensive pro-inflammatory conditions of the host by promoting the M2-phenotype of monocytes, probably through haemozoin-induced CD206 expression [7, 8]. In addition to the direct impact of new drug candidates on pathogens, maintenance and promotion of immune responses are also important to overcome emerging pathogen resistance. Modulating the immune system is a promising approach to boost host defence mechanisms and increases the clearance of pathogens while minimizing tissue damage from inflammation. It has been shown that several antibiotics are able to modulate inflammatory processes and thereby promote pathogen defence even in the face of mechanisms to resist the direct antimicrobial impact of the drugs [9]. Therefore, immunomodulation can expand the efficacy profile and may unfold new therapeutic indications as a pro- or antiinflammatory modulator. Inflammation accompanies the majority of infections, regardless of whether they are caused by bacteria or parasites, and is characterized by the accumulation of various immune cells such as neutrophils, dendritic cells, monocytes, and macrophages at the site of infection [10]. This can result in the release of a variety of lipid mediators, cytokines, chemokines, growth factors, and enzymes that mediate pathogen killing but can also lead to bystander tissue injuries. In order to prevent an exaggerated immune response and protect the host tissue, a well-timed resolution of the inflammatory process is mandatory. Macrophages are essential for the local initiation of inflammation since they release several cytokines such as interleukin (IL)-1β, interferon (IFN)-γ, IL-23, and tumour necrosis factor (TNF)-α. Furthermore, they recruit additional immune cells by secreting chemokines such as CC-chemokine ligand (CCL)2, C-X-C motif chemokine (CXCL)10, and CXCL8 [11]. Besides activating the inflammatory process, macrophages recognize and ingest pathogens and activate T cells via HLA-DR. During the resolution of inflammation, macrophages release growth factors, cytokines (e.g. IL-10 and IL-4), and chemokines (e.g. CCL18 and CCL17) to recruit anti-inflammatory TH2 and Treg cells to support the tissue healing process [11–14]. The immune response is regulated not only by macrophages but also by dendritic cells. The expression of specific surface markers such as CD40, CD80, CD86, and HLA-DR is essential for the presentation of antigens and the regulation of the antigen-specific T cell response by dendritic cells. Since macrophages and dendritic cells are important players in the fight against Plasmodium falciparum [15], we focused on these cell types. In malaria, excessive production of inflammatory cytokines, including TNF-α, IL-6, IL-12, and IFN-γ, at the early stages of infection is a key contributor to pathogenesis [16]. Mouse studies revealed that specifica (...truncated)