News and Highlights

On this page we present recently published research carried out by SSEP members

Overproduction of H2S, generated by CBS, inhibits mitochondrial Complex IV and suppresses oxidative phosphorylation in Down syndrome

Panagaki T, Randi EB, Augsburger F, and Szabo C

(2019) Proc Natl Acad Sci U S A, 116(38):18769-18771

In Down Syndrome there is an extra 21st chromosome in the cells, which produces many extra proteins, leading to severe biochemical problems. One of these extra proteins is an enzyme called CBS. This enzyme has important physiological roles: it gets rid off some potentially toxic metabolites (e.g. homocysteine), but it also makes a biological gas called H2S. In the Down Syndrome cells, too much H2S produced, and at this level, H2S is toxic. The current paper shows that this excess H2S inhibits the ability of the mitochondria (a cell organelle that specializes in making ATP, the 'currency' of energy in our cells) to move electrons. When the H2S homeostasis is normalized (by deleting CBS or pharmacologically inhibiting its ability to make H2S), the "toxic H2S gas cloud" can be lifted and the cells regained their ability to produce energy. The findings give us hope that that future, therapeutic inhibition of CBS may improve metabolic, neuronal, or possibly cognitive function in Down Syndrome.

***

The architecture of the IgG anti-carbohydrate repertoire in primary antibody deficiencies (PADs)

Jandus P, Frias Boligan K, Smith DF, de Graauw E, Grimbacher B, Jandus C, Abdelhafez MM, Despont A, Bovin N, Simon D, Rieben R, Simon HU, Cummings RD, von Gunten S.

(2019) Blood.2019 Sep 19. pii: blood.2019001705

The surface of each living cell, including microbial pathogens and tumor cells,is coated with a variety of often characteristic glycans, which can be recognized by glycan-specific antibodies. Given the importance of antibodies in immune defence, an atlas of the glycan-specific IgG repertoire in primary antibody deficiency (PAD) was established. Patients with certain types of PAD exhibited a significant lack of IgG antibodies to bacterial antigens. Furthermore, a lack of naturally-occurring tumour-specific antibodies was found in patient subsets known to be at increased risk to develop malignancies. On the other hand, the observed lack of Gal-alpha IgG antibodies in PAD patients suggested tolerance for xenotransplants, which was confirmed in functional experiments. Taken together, we identified significant differences in the architecture of the glycan-specific IgG antibody repertoire, which may have important implications for diagnostics, preventive and therapeutic avenues and the clinical course in immunodeficiencies.

***

Siglec-9 regulates an effector memory CD8+T-cell subset that congregates in the melanoma tumor microenvironment

Haas Q, Boligan KF, Jandus C, Schneider C, Simillion C, Stanczak MA, Haubitz M, Seyed Jafari SM, Zippelius A, Baerlocher GM, Läubli H, Hunger RE, Romero P, Simon HU, von Gunten S.

(2019) Cancer Immunol Res 7(5):707-718

Tumors are known to exhibit altered surface glycosylation patterns, which have functional implications. In this study, it wasdemonstrated that hypersialylation,one of the most common tumor glycosylation changes, preventsefficient immune attack by cytotoxic CD8+T cells. This attenuation of T cell anti-tumor responses was shown to involve the interaction of tumor-associated carbohydrate antigens (TACA) with the inhibitory Siglec-9 receptor, which in melanoma was up-regulated on tumor-infiltrating effector memory T cells. This work highlights the role of tumor glycosylation interaction with glycan-binding proteins (GBP) as a further immune checkpoint that might be targeted for improved immunotherapeutic interventionsfor the treatment of cancer.

Cover story May 2019

***

2018 and older

Identification of potent and selective small molecule inhibitors of the cation channel TRPM4

Ozhathil LC, Delalande C, Bianchi B, Nemeth G, Kappel S, Thomet U, Ross-Kaschitza D, Simonin C, Rubin M, Gertsch J, Lochner M, Peinelt C, Reymond JL, Abriel H

(2018) Br J Pharmacol, 10.1111/bph.14220

Ion channels are membrane proteins found in virtually every cell allowing the passage of different ions such as Na+, K+ and Ca2+ and Cl-. Many drugs are modulating their function. In this study, we looked for new chemical compounds able to block the ion channel called TRPM4 found at the membrane of many cell types such as cardiac and cancer cells. In particular, we developed a novel fluorescence-based cellular assay and screened a library of ~800 compounds to identify a potent and selective blocker of TRPM4 channel. Our data also demonstrate that the identified compound in addition to being a blocker of TRPM4 also rescues the membrane trafficking of TRPM4 loss-of-expression mutants found in cardiac patients. The new chemical structure identified in our study will be useful to understand the role of TRPM4 in disease and possibly develop new clinical drug candidates.

***

ROS and glutathionylation balance cytoskeletal dynamics in neutrophil extracellular trap formation

Stojkov D, Amini P, Oberson K, Sokollik C, Duppenthaler A, Simon HU, Yousefi S

(2017) J Cell Biol 216: 4073-4090

Neutrophils represent the most prominent cells in the blood circulation and their antimicrobial defense activity has been defined by their ability to phagocytose microbes or to form Neutrophil Extracellular Traps (NETs) that can entrap and kill bacteria in the extracellular space. In our present manuscript, we report novel findings which indicate that a dynamic intracellular transport by the cytoskeleton plays a role in bringing granule proteins and mitochondrial DNA together to form NETs. Our data also demonstrate that reactive oxygen species (ROS), generated by the enzyme NADPH oxidase, act as signaling molecules involved in the regulation of the cytoskeleton. Overall, our work suggests that the activation of actin polymerization might be a new strategy for improving neutrophil function in NADPH oxidase deficiency.

***

BH3 mimetics efficiently induce apoptosis in mouse basophils and mast cells

Reinhart R, Rohner L, Wicki S, Fux M, Kaufmann T

(2018) Cell Death Differ 25: 204-216

Basophils and mast cells are known to play critical roles in the pathogenesis of diverse allergic diseases. The survival of both cell types seems to strongly depend on distinct pro-survival proteins of the Bcl-2 family. We thus hypothesized that a novel class of small molecule inhibitors specifically targeting individual Bcl-2 family members, co-called BH3 mimetics, may be useful to induce apoptosis in naïve or activated basophils and mast cells. Indeed, our work revealed the crucial importance of BCL-2 and BCL-XL for survival of in vitro differentiated mouse basophils, whereas mouse mast cells and human basophils highly depended on BCL-2 and MCL-1, respectively. Cell survival was strongly increased by the key cytokine IL-3, but this effect could still be counteracted by the right combination of BH3 mimetic compounds. In conclusion, our results indicate that BH3 mimetics, besides their application in anti-cancer therapy, may have a potential worthwhile exploring in the treatment of basophil and mast cell mediated allergic disorders.

***

Evidence of an abnormal epithelial barrier in active, untreated and corticosteroid-treated eosinophilic esophagitis

Simon D, Page B, Vogel M, Bussmann C, Blanchard C, Straumann A, Simon HU

(2017) Allergy, 10.1111/all.13244

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease characterized by symptoms related to esophageal dysfunction and an eosinophil-predominant inflammation. Here, we asked the question whether Candida albicans colonization and sensitization observed in pediatric and adult EoE patients is the consequence of an epithelial dysfunction associated with the disease and/or is a consequence of the treatment with corticosteroids (CS) that is the first line therapy for EoE. Using immunofluorescence techniques on esophageal tissue sections, we observed increased numbers of eosinophils and mast cells, higher expression levels of alarmins, antimicrobial peptides, and proteases in EoE as compared with controls, while reduced expression of a protease inhibitor and barrier proteins, i.e. filaggrin, E-cadherin, claudin, occludin, demoglein-1 was found, independent of CS therapy. CS seemed to have selective effects on improving the epithelial barrier. Instead, CS reduced the expression of cathelicidin as well as the numbers of LHC and eosinophils, thereby possibly even further promoting Candida albicans colonization and invasion.

***

IVIG regulates the survival of human but not mouse neutrophils

Schneider C, Wicki S, Graeter S, Timcheva TM, Keller CW, Quast I, Leontyev D, Djoumerska-Alexieva IK, Kasermann F, Jakob SM, Dimitrova PA, Branch DR, Cummings RD, Lunemann JD, Kaufmann T, Simon HU, von Gunten S

(2017) Sci Rep 7: 1296

Intravenous immunoglobulin (IVIG) has anti-inflammatory effects when administered at high concentrations to patients with chronic inflammatory and autoimmune disorders. IVIG is a pluripotent drug and a number of immunoregulatory mechanisms have been described including induced cell death of activated neutrophils. Schneider C et al. found that latter mechanism is specific, Fab but not Fc-mediated, and occurs in human, but not mouse neutrophils. In addition to xenogeneic effects of human IVIG if used in mice, this finding highlights potential species-differences in the mechanisms of IVIG action depending on the experimental disease model in vivo.

***

Conformational dynamics and role of the acidic pocket in ASIC pH-dependent gating

Vullo S, Bonifacio G, Roy S, Johner N, Berneche S, Kellenberger S

(2017) Proc Natl Acad Sci U S A 114: 3768-3773

Acid-sensing ion channels (ASICs) are neuronal Na channels that are activated by a drop in extracellular pH. They contribute to physiological and pathological processes such as learning, fear and pain sensation, and neuronal death after ischemic stroke. Although ASICs are potentially interesting drug targets, their activation mechanism is only poorly understood. This study shows that pH sensing in a channel domain that had been proposed as the ligand binding site of ASICs, the “acidic pocket”, has only a modulatory, but not an essential role for the activation of these channels. The study further describes the mechanisms of the ASIC regulation by the acidic pocket, which remains an interesting target site for drug candidates acting on ASICs.

Your article could stand here ! Let us know if you have recently published exciting research results that are of a major impact and that could be of interest to other SSEP members.