Reporting Psychiatric Disease Characteristics in Post-Mortem- and Biological Research.

Inflammation is a prominent hypothesis in the neurobiology of depression. In our transcriptomic profiling study of microglia in chronic major depressive disorder (MDD), we revealed a distinct disease-associated microglia (DAM) transcriptomic profile exclusively found in cortical gray matter, that we have designated DepDAM. These DepDAM revealed an immune-suppressed state, with a possible upstream mechanism for microglial suppression, by upregulation of CD200 and CD47 ("don't eat me signals") located on synapses.

Microglia Transcriptional Profiling in Major Depressive Disorder Shows Inhibition of Cortical Gray Matter Microglia.

Background: Microglia have been implicated in the pathophysiology of major depressive disorder (MDD), but information on biological mechanisms is limited. Therefore, we investigated the gene expression profile of microglial cells in relation to neuronal regulators of microglia activity in well-characterized MDD and control autopsy brains.

Methods: Pure, intact microglia were isolated at brain autopsy from occipital cortex gray matter (GM) and corpus callosum white matter of 13 donors with MDD and 10 age-matched control donors for RNA sequencing.

Selective emergence of antibody-secreting cells in the multiple sclerosis brain.

Background: Although distinct brain-homing B cells have been identified in multiple sclerosis (MS), it is unknown how these further evolve to contribute to local pathology. We explored B-cell maturation in the central nervous system (CNS) of MS patients and determined their association with immunoglobulin (Ig) production, T-cell presence, and lesion formation.

Methods: Ex vivo flow cytometry was performed on post-mortem blood, cerebrospinal fluid (CSF), meninges and white matter from 28 MS and 10 control brain donors to characterize B cells and antibody-secreting cells (ASCs).

The adhesion G protein-coupled receptor GPR56/ADGRG1 in cytotoxic lymphocytes.

GPR56/ADGRG1 is an adhesion G protein-coupled receptor connected to brain development, haematopoiesis, male fertility, and tumorigenesis. Nevertheless, expression of GPR56 is not restricted to developmental processes. Studies over the last years have demonstrated a marked presence of GPR56 in human cytotoxic NK and T cells.

Osteopontin associates with brain T-cell transcriptome and compartmentalization in donors with and without multiple sclerosis.

The human brain is populated by perivascular T cells with a tissue-resident memory T (T)-cell phenotype, which in multiple sclerosis (MS) associate with lesions. We investigated the transcriptional and functional profile of freshly isolated T cells from white and gray matter. RNA sequencing of CD8 and CD4 CD69 T cells revealed T-cell signatures.

T-cell surveillance of the human brain in health and multiple sclerosis.

Circulating and tissue-resident T cells collaborate in the protection of tissues against harmful infections and malignant transformation but also can instigate autoimmune reactions. Similar roles for T cells in the brain have been less evident due to the compartmentized organization of the central nervous system (CNS). In recent years, beneficial as well as occasional, detrimental effects of T-cell-targeting drugs in people with early multiple sclerosis (MS) have increased interest in T cells patrolling the CNS.

Adhesion GPCR GPR56 Expression Profiling in Human Tissues.

Despite the immense functional relevance of GPR56 (gene ) in highly diverse (patho)physiological processes such as tumorigenesis, immune regulation, and brain development, little is known about its exact tissue localization. Here, we validated antibodies for GPR56-specific binding using cells with tagged GPR56 or eliminated in immunotechniques. Using the most suitable antibody, we then established the human GPR56 tissue expression profile.

The Inhibitory Receptor GPR56 () Is Specifically Expressed by Tissue-Resident Memory T Cells in Mice But Dispensable for Their Differentiation and Function In Vivo.

Tissue-resident memory T (T) cells with potent antiviral and antibacterial functions protect the epithelial and mucosal surfaces of our bodies against infection with pathogens. The strong proinflammatory activities of T cells suggest requirement for expression of inhibitory molecules to restrain these memory T cells under steady state conditions. We previously identified the adhesion G protein-coupled receptor GPR56 as an inhibitory receptor of human cytotoxic lymphocytes that regulates their cytotoxic effector functions.

Simulation of Onset of the Capillary Surface Wave in the Ultrasonic Atomizer.

The novel drug delivery system refers to the formulations and technologies for transporting a pharmaceutical compound in the body as it is needed to safely achieve its desired therapeutic effects. In this study, the onset vibrational amplitude of capillary surface waves for ultrasonic atomization spray is explained based on Faraday instability. Using ultrasonic frequency, the vibrational amplitude approached a critical point, and the liquid surface broke up into tiny drops.

Multiple Targets for Oxysterols in Their Regulation of the Immune System.

Oxysterols, or cholesterol oxidation products, are naturally occurring lipids which regulate the physiology of cells, including those of the immune system. In contrast to effects that are mediated through nuclear receptors or by epigenetic mechanism, which take tens of minutes to occur, changes in the activities of cell-surface receptors caused by oxysterols can be extremely rapid, often taking place within subsecond timescales. Such cell-surface receptor effects of oxysterols allow for the regulation of fast cellular processes, such as motility, secretion and endocytosis.

GPCRomics of Homeostatic and Disease-Associated Human Microglia.

G-protein-coupled receptors (GPCRs) are critical sensors affecting the state of eukaryotic cells. To get systematic insight into the GPCRome of microglia, we analyzed publicly available RNA-sequencing data of bulk and single cells obtained from human and mouse brains. We identified 17 rhodopsin and adhesion family GPCRs robustly expressed in microglia from human brains, including the homeostasis-associated genes , , , , , and .

White matter lesions in multiple sclerosis are enriched for CD20 CD8 tissue-resident memory T cells.

Brain CD8 CD69 tissue-resident memory T (T ) cells comprise a CD20 subset, which is proportionally larger in CD103-negative T cells. In multiple sclerosis (MS) lesions, CD20 T -cell proportions are increased. CD20-expression is associated with higher levels of CXCR6, Ki-67, and granzyme B, supporting CD20 T cells as a relevant subset in MS.

Single-cell mass cytometry reveals complex myeloid cell composition in active lesions of progressive multiple sclerosis.

Myeloid cells contribute to inflammation and demyelination in the early stages of multiple sclerosis (MS), but it is still unclear to what extent these cells are involved in active lesion formation in progressive MS (PMS). Here, we have harnessed the power of single-cell mass cytometry (CyTOF) to compare myeloid cell phenotypes in active lesions of PMS donors with those in normal-appearing white matter from the same donors and control white matter from non-MS donors. CyTOF measurements of a total of 74 targeted proteins revealed a decreased abundance of homeostatic and TNF microglia, and an increase in highly phagocytic and activated microglia states in active lesions of PMS donors.

Perivascular tissue resident memory T cells as therapeutic target in multiple sclerosis.

Introduction: Multiple sclerosis (MS) is characterized by inflammatory attacks of infiltrating leukocytes at onset but evolves into a smoldering, progressive disease within the central nervous system at its later stages. The authors discuss the contribution of white matter lesions to the pathology of advanced MS, thereby paying particular attention to the role of T cells.

Areas Covered: Diagnostic biopsy and autopsy studies of white matter lesions in early MS show different pathological patterns of demyelination and leukocyte infiltration.

Tissue-resident memory T cells invade the brain parenchyma in multiple sclerosis white matter lesions.

Multiple sclerosis is a chronic inflammatory, demyelinating disease, although it has been suggested that in the progressive late phase, inflammatory lesion activity declines. We recently showed in the Netherlands Brain Bank multiple sclerosis-autopsy cohort considerable ongoing inflammatory lesion activity also at the end stage of the disease, based on microglia/macrophage activity. We have now studied the role of T cells in this ongoing inflammatory lesion activity in chronic multiple sclerosis autopsy cases.

The expanding functional roles and signaling mechanisms of adhesion G protein-coupled receptors.

The adhesion class of G protein-coupled receptors (GPCRs) is the second largest family of GPCRs (33 members in humans). Adhesion GPCRs (aGPCRs) are defined by a large extracellular N-terminal region that is linked to a C-terminal seven transmembrane (7TM) domain via a GPCR-autoproteolysis inducing (GAIN) domain containing a GPCR proteolytic site (GPS). Most aGPCRs undergo autoproteolysis at the GPS motif, but the cleaved fragments stay closely associated, with the N-terminal fragment (NTF) bound to the 7TM of the C-terminal fragment (CTF).

Transcriptional profiling of human microglia reveals grey-white matter heterogeneity and multiple sclerosis-associated changes.

Here we report the transcriptional profile of human microglia, isolated from normal-appearing grey matter (GM) and white matter (WM) of multiple sclerosis (MS) and non-neurological control donors, to find possible early changes related to MS pathology. Microglia show a clear region-specific profile, indicated by higher expression of type-I interferon genes in GM and higher expression of NF-κB pathway genes in WM. Transcriptional changes in MS microglia also differ between GM and WM.

The Adhesion G Protein-Coupled Receptor GPR97/ Is Expressed in Human Granulocytes and Triggers Antimicrobial Effector Functions.

The adhesion family of G protein-coupled receptors (aGPCRs) comprises 33 members in human, several of which are distinctly expressed and functionally involved in polymorphonuclear cells (PMNs). As former work indicated the possible presence of the aGPCR GPR97 in granulocytes, we studied its cellular distribution, molecular structure, signal transduction, and biological function in PMNs. RNA sequencing and mass-spectrometry revealed abundant RNA and protein expression of ADGRG3/GPR97 in granulocyte precursors and terminally differentiated neutrophilic, eosinophilic, and basophilic granulocytes.

Adhesion GPCRs in Regulating Immune Responses and Inflammation.

The adhesion family comprises one of the five major clades of G protein-coupled receptors (GPCRs). Unlike conventional GPCRs, adhesion GPCRs (aGPCRs) have extended ectodomains with various protein folds that facilitate protein-protein interactions and, hence, putative cellular adhesive functions. Juxtaposed to the seven-pass transmembrane domain is a GPCR autoproteolysis-inducing domain that enables autoproteolytic cleavage of the receptor, resulting in a bipartite structure of many aGPCRs.

Adhesion GPCRs as Modulators of Immune Cell Function.

Immune cells express several adhesion G protein-coupled receptors (aGPCRs), including the ADGRE subfamily members EMR1 (F4/80, ADGRE1), EMR2 (ADGRE2), EMR3 (ADGRE3), EMR4 (FIRE, ADGRE4), and CD97 (ADGRE5), the ADGRB subfamily member BAI1 (ADGRB1), and the ADGRG subfamily members GPR56 (ADGRG1), GPR97 (Pb99, ADGRG3), and GPR114 (ADGRG5). Expression of these molecules in hematopoietic stem and progenitor cells, monocytes/macrophages (Mφs), dendritic cells, granulocytes, and lymphocytes depends on lineage diversification and maturation, making them suitable markers for individual leukocyte subsets (e.g.

Intracellular delivery of poly(I:C) induces apoptosis of fibroblast-like synoviocytes via an unknown dsRNA sensor.

Fibroblast-like synoviocytes (FLS) express functional membranous and cytoplasmic sensors for double-stranded (ds)RNA. Notably, FLS undergo apoptosis upon transfection with the synthetic dsRNA analog poly(I:C). We here studied the mechanism of intracellular poly(I:C) recognition and subsequent cell death in FLS.