Mrgprb2-dependent Mast Cell Activation Plays a Crucial Role in Acute Colitis.

Background & Aims: Mast cells (MCs) are typically found at mucosal surfaces, where their immunoglobulin E (IgE)-dependent activation plays a central role in allergic diseases. Over the past years, signaling through Mas-related G protein-coupled receptor b2 (Mrgprb2) in mice and MRGPRX2 in humans has gained a lot of interest as an alternative MC activation pathway with high therapeutic potential. The aim of this study was to explore the relevance of such IgE-independent, Mrgprb2-mediated signaling in colonic MCs in the healthy and acutely inflamed mouse colon.

Serum Amyloid A3 Fuels a Feed-Forward Inflammatory Response to the Bacterial Amyloid Curli in the Enteric Nervous System.

Background & Aims: Mounting evidence suggests the gastrointestinal microbiome is a determinant of peripheral immunity and central neurodegeneration, but the local disease mechanisms remain unknown. Given its potential relevance for early diagnosis and therapeutic intervention, we set out to map the pathogenic changes induced by bacterial amyloids in the gastrointestinal tract and its enteric nervous system.

Methods: To examine the early response, we challenged primary murine myenteric networks with curli, the prototypical bacterial amyloid, and performed shotgun RNA sequencing and multiplex enzyme-linked immunosorbent assay.

Protocol for xenografting of BxPC-3 pancreatic tumors using a chorioallantoic membrane model.

The chorioallantoic membrane (CAM) model is an increasingly attractive model for the study of human tumors. However, concise techniques for the use of pancreatic ductal adenocarcinoma BxPC-3 xenografts in CAM assays are not yet available. Here, we present a protocol for the induction of BxPC-3 xenograft tumors with high grafting efficiency.

Cerebral microvascular endothelial cell-derived extracellular vesicles regulate blood - brain barrier function.

Autoreactive T lymphocytes crossing the blood-brain barrier (BBB) into the central nervous system (CNS) play a crucial role in the initiation of demyelination and neurodegeneration in multiple sclerosis (MS). Recently, extracellular vesicles (EV) secreted by BBB endothelial cells (BBB-EC) have emerged as a unique form of cell-to-cell communication that contributes to cerebrovascular dysfunction. However, the precise impact of different size-based subpopulations of BBB-EC-derived EV (BBB-EV) on the early stages of MS remains unclear.

Behavioral and Neuropathological Phenotyping of the Tau58/2 and Tau58/4 Transgenic Mouse Models for FTDP-17.

Background: The Tau58/2 and Tau58/4 mouse lines expressing 0N4R tau with a P301S mutation mimic aspects of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). In a side-by-side comparison, we report the age-dependent development of cognitive, motor, and behavioral deficits in comparison with the spatial-temporal evolution of cellular tau pathology in both models.

Methods: We applied the SHIRPA primary screen and specific neuromotor, behavioral, and cognitive paradigms.

Structural characterization of human urea transporters UT-A and UT-B and their inhibition.

In this study, we present the structures of human urea transporters UT-A and UT-B to characterize them at molecular level and to detail the mechanism of UT-B inhibition by its selective inhibitor, UTB-14. High-resolution structures of both transporters establish the structural basis for the inhibitor's selectivity to UT-B, and the identification of multiple binding sites for the inhibitor will aid with the development of drug lead molecules targeting both transporters. Our study also discovers phospholipids associating with the urea transporters by combining structural observations, native MS, and lipidomics analysis.

The orphan MRGPRF receptor is expressed in entero-endocrine cells of the human gut mucosa.

In the past years, it has become clear that the family of Mas-related G protein-coupled receptors plays a central role in neuro-immune communication at mucosal barrier surfaces, in particular in the skin. Remarkably, MRGPR expression at other mucosal surfaces remains poorly characterized. To fill this gap in our understanding, the present study was undertaken to screen and verify the expression of the human MRGPR family members in the mucosal biopsies of the human gastrointestinal (GI) tract.

The pulmonary neuroepithelial body microenvironment represents an underestimated multimodal component in airway sensory pathways.

Exciting new imaging and molecular tools, combined with state-of-the-art genetically modified mouse models, have recently boosted interest in pulmonary (vagal) sensory pathway investigations. In addition to the identification of diverse sensory neuronal subtypes, visualization of intrapulmonary projection patterns attracted renewed attention on morphologically identified sensory receptor end-organs, such as the pulmonary neuroepithelial bodies (NEBs) that have been our area of expertise for the past four decades. The current review aims at providing an overview of the cellular and neuronal components of the pulmonary NEB microenvironment (NEB ME) in mice, underpinning the role of these complexly organized structures in the mechano- and chemosensory potential of airways and lungs.

The autonomic nervous system from a morphofunctional perspective: Historical overview and current concepts over the last two centuries highlighting contributions from Eastern Europe.

The present contribution comprises both an introductory comment and an overview of the contributions within this special issue on historical and current research on the autonomic nervous system from Eastern European colleagues, particularly focusing on the autonomic innervation of the gastrointestinal tract and of the cardiovascular system. It also gives a selected overview of interesting and seminal papers on these topics that appeared in The Anatomical Record since its foundation in 1906.

Mas-related G protein-coupled receptor MRGPRX2 in human basophils: Expression and functional studies.

Background: Occupancy of MRGPRX2 heralds a new era in our understandings of immediate drug hypersensitivity reactions (IDHRs), but a constitutive expression of this receptor by basophils is debated.

Objective: To explore the expression and functionality of MRGPRX2 in and on basophils.

Methods: Basophils from patients with birch pollen allergy, IDHRs to moxifloxacin, and healthy controls were studied in different conditions, that is, in rest, after stimulation with anti-IgE, recombinant major birch pollen allergen (rBet v 1), moxifloxacin, fMLP, substance P (SP), or other potential basophil secretagogues.

Mas-Related G Protein-Coupled Receptors (Mrgprs) as Mediators of Gut Neuro-Immune Signaling.

Over the past 15 years, the research field on Mas-related G protein-coupled receptors (Mrgprs), a relatively new family of rhodopsin A-like G protein-coupled receptors, has expanded enormously, and a plethora of recent studies have provided evidence that several of these Mrgpr family members play an important role in the underlying mechanisms of itch and pain, as well as in the initiation and modulation of inflammatory/allergic responses. Initial studies mainly focused on the skin, but more recently also visceral organs such as the respiratory and gastrointestinal (GI) tracts emerged as sites for Mrgpr involvement. It has become clear that the gastrointestinal tract and its innervation in close association with the immune system represent a novel expression site for Mrgprs where they contribute to the interoceptive mechanisms maintaining homeostasis and might constitute promising targets in chronic abdominal pain disorders.

Impact of pulmonary African trypanosomes on the immunology and function of the lung.

Approximately 20% of sleeping sickness patients exhibit respiratory complications, however, with a largely unknown role of the parasite. Here we show that tsetse fly-transmitted Trypanosoma brucei parasites rapidly and permanently colonize the lungs and occupy the extravascular spaces surrounding the blood vessels of the alveoli and bronchi. They are present as nests of multiplying parasites exhibiting close interactions with collagen and active secretion of extracellular vesicles.

Enteric glial cells favor accumulation of anti-inflammatory macrophages during the resolution of muscularis inflammation.

Monocyte-derived macrophages (Mφs) are crucial regulators during muscularis inflammation. However, it is unclear which micro-environmental factors are responsible for monocyte recruitment and anti-inflammatory Mφ differentiation in this paradigm. Here, we investigate Mφ heterogeneity at different stages of muscularis inflammation and determine how environmental cues can attract and activate tissue-protective Mφs.

Neuro-immune interactions and the role of Mas-related G protein-coupled receptors in the gastrointestinal tract.

Over the past decade, the research field dealing with the role of a new family of Rhodopsin A-like G protein-coupled receptors, that is, the family of Mas-related G protein-coupled receptors (Mrgprs) has expanded enormously. A plethora of recent studies have provided evidence that Mrgprs are key players in itch and pain, as well as in the initiation and modulation of inflammatory/allergic responses in the skin. Over the years, it has become clear that this role is not limited to the skin, but extends to other mucosal surfaces such as the respiratory tract and the gastrointestinal (GI) tract.

Hyperthermia Enhances Efficacy of Chemotherapeutic Agents in Pancreatic Cancer Cell Lines.

Chemotherapy (CT) is the standard care for advanced pancreatic ductal adenocarcinoma (PDAC); however, with limited efficacy. Hyperthermia (HT) treatment has been suggested as a sensitizer to improve outcomes. However, the direct effect of the HT and CT combination is not fully understood.

Oligodendroglia-derived extracellular vesicles activate autophagy via LC3B/BAG3 to protect against oxidative stress with an enhanced effect for HSPB8 enriched vesicles.

Background: The contribution of native or modified oligodendroglia-derived extracellular vesicles (OL-EVs) in controlling chronic inflammation is poorly understood. In activated microglia, OL-EVs contribute to the removal of cytotoxic proteins following a proteotoxic stress. Intracellular small heat shock protein B8 (HSPB8) sustain this function by facilitating autophagy and protecting cells against oxidative stress mediated cell death.

TNF-α-Secreting Lung Tumor-Infiltrated Monocytes Play a Pivotal Role During Anti-PD-L1 Immunotherapy.

Immune checkpoint blockade (ICB) of the PD-1 pathway revolutionized the survival forecast for advanced non-small cell lung cancer (NSCLC). Yet, the majority of PD-L1 NSCLC patients are refractory to anti-PD-L1 therapy. Recent observations indicate a pivotal role for the PD-L1 tumor-infiltrating myeloid cells in therapy failure.

Luminescent Human iPSC-Derived Neurospheroids Enable Modeling of Neurotoxicity After Oxygen-glucose Deprivation.

Despite the considerable impact of stroke on both the individual and on society, a neuroprotective therapy for stroke patients is missing. This is partially due to the current lack of a physiologically relevant human in vitro stroke model. To address this problem, we have developed a luminescent human iPSC-derived neurospheroid model that enables real-time read-out of neural viability after ischemia-like conditions.

Vasoconstrictor antagonism improves functional and structural vascular alterations and liver damage in rats with early NAFLD.

Background & Aims: Intrahepatic vascular resistance is increased in early non-alcoholic fatty liver disease (NAFLD), potentially leading to tissue hypoxia and triggering disease progression. Hepatic vascular hyperreactivity to vasoconstrictors has been identified as an underlying mechanism. This study investigates vasoconstrictive agonism and antagonism in 2 models of early NAFLD and in non-alcoholic steatohepatitis (NASH).

Constitutive, Basal, and β-Alanine-Mediated Activation of the Human Mas-Related G Protein-Coupled Receptor D Induces Release of the Inflammatory Cytokine IL-6 and Is Dependent on NF-κB Signaling.

G protein-coupled receptors (GPCRs) have emerged as key players in regulating (patho)physiological processes, including inflammation. Members of the Mas-related G protein coupled receptors (MRGPRs), a subfamily of GPCRs, are largely expressed by sensory neurons and known to modulate itch and pain. Several members of MRGPRs are also expressed in mast cells, macrophages, and in cardiovascular tissue, linking them to pseudo-allergic drug reactions and suggesting a pivotal role in the cardiovascular system.

Miltefosine enhances infectivity of a miltefosine-resistant Leishmania infantum strain by attenuating its innate immune recognition.

Background: Miltefosine (MIL) is currently the only oral drug available to treat visceral leishmaniasis but its use as first-line monotherapy has been compromised by an increasing treatment failure. Despite the scarce number of resistant clinical isolates, MIL-resistance by mutations in a single aminophospholipid transporter gene can easily be selected in a laboratory environment. These mutations result in a reduced survival in the mammalian host, which can partially be restored by exposure to MIL, suggesting a kind of drug-dependency.