Membrane-spanning 4-domains Research Articles

Hepatic danger signaling triggers TREM2+ macrophage induction and drives steatohepatitis via MS4A7-dependent inflammasome activation.

Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), is an advanced stage of metabolic fatty liver disease. The pathogenic mechanisms of MASH center on hepatocyte injury and the ensuing immune response within the liver microenvironment. Recent work has implicated TREM2+ macrophages in various disease conditions, and substantial induction of TREM2+ NASH-associated macrophages (NAMs) serves as a hallmark of metabolic liver disease. Despite this, the mechanisms through which NAMs contribute to MASH pathogenesis remain poorly understood. Here, we identify membrane-spanning 4-domains a7 (MS4A7) as a NAM-specific pathogenic factor that exacerbates MASH progression in mice. Hepatic MS4A7 expression was strongly induced in mouse and human MASH and associated with the severity of liver injury. Whole-body and myeloid-specific ablation of Ms4a7 alleviated diet-induced MASH pathologies in male mice. We demonstrate that exposure to lipid droplets (LDs), released upon injury of steatotic hepatocytes, triggered NAM induction and exacerbated MASH-associated liver injury in an MS4A7-dependent manner. Mechanistically, MS4A7 drove NLRP3 inflammasome activation via direct physical interaction and shaped disease-associated cell states within the liver microenvironment. This work reveals the LD-MS4A7-NLRP3 inflammasome axis as a pathogenic driver of MASH progression and provides insights into the role of TREM2+ macrophages in disease pathogenesis.

Transcriptomic survey of key reproductive and metabolic tissues in mouse models of polycystic ovary syndrome

Excessive androgen production and obesity are key to polycystic ovary syndrome (PCOS) pathogenesis. Prenatal androgenized (PNA), peripubertal androgenized, and overexpression of nerve growth factor in theca cells (17NF) are commonly used PCOS-like mouse models and diet-induced maternal obesity model is often included for comparsion. To reveal the molecular features of these models, we have performed transcriptome survey of the hypothalamus, adipose tissue, ovary and metaphase II (MII) oocytes. The largest number of differentially expressed genes (DEGs) is found in the ovaries of 17NF and in the adipose tissues of peripubertal androgenized models. In contrast, hypothalamus is most affected in PNA and maternal obesity models suggesting fetal programming effects. The Ms4a6e gene, membrane-spanning 4-domains subfamily A member 6E, a DEG identified in the adipose tissue in all mouse models is also differently expressed in adipose tissue of women with PCOS, highlighting a conserved disease function. Our comprehensive transcriptomic profiling of key target tissues involved in PCOS pathology highlights the effects of developmental windows for androgen exposure and maternal obesity, and provides unique resource to investigate molecular mechanisms underlying PCOS pathogenesis.

MS4A15 acts as an oncogene in ovarian cancer through reprogramming energy metabolism

Membrane-spanning 4-domains subfamily A 15 (MS4A15) belongs to transmembrane proteins and has been recognized as a regulator of various biological events including cell metabolism. Dysregulation of cell metabolism is a component of malignant transformation in numerous types of tumors, including ovarian cancer (OC). Nevertheless, whether MS4A15 is involved in OC progression remains obscure, as well as the underlying mechanisms. In the present study, we found that MS4A15 expression was significantly up-regulated in tumor tissues from OC patients compared with the matched normal adjacent samples. Higher MS4A15 expression predicted poorer overall survival rate in patients with OC. Our in vitro studies subsequently showed that MS4A15 knockdown markedly reduced the proliferation of OC cells, while its over-expression accelerated the proliferative capacity of OC cells through mediating the progression of G0/G1 cell cycle. Consistently, stable MS4A15 knockdown strongly inhibited the tumor growth in the established xenograft mouse models, along with evidently decreased expression of KI-67 positive staining. However, xenograft mouse models with MS4A15 over-expression exerted significantly accelerated tumor growth rates. We then found that MS4A15 reprogrammed energy metabolism to enhance OC progression. Under normal status, MS4A15 enhanced de novo lipid synthesis in OC cells. Upon glucose starvation, MS4A15 elevated oxidative phosphorylation (OXPHOS) to protect OC cells from starvation-induced cell death. Taken together, our findings demonstrated that MS4A15 may play an essential role in promoting OC growth mainly via reprogramming energy metabolism, and thus could be considered as a novel therapeutic target for OC treatment.

TMEM176B Regulates AKT/mTOR Signaling and Tumor Growth in Triple-Negative Breast Cancer.

TMEM176B is a member of the membrane spanning 4-domains (MS4) family of transmembrane proteins, and a putative ion channel that is expressed in immune cells and certain cancers. We aimed to understand the role of TMEM176B in cancer cell signaling, gene expression, cell proliferation, and migration in vitro, as well as tumor growth in vivo. We generated breast cancer cell lines with overexpressed and silenced TMEM176B, and a therapeutic antibody targeting TMEM176B. Proliferation and migration assays were performed in vitro, and tumor growth was evaluated in vivo. We performed gene expression and Western blot analyses to identify the most differentially regulated genes and signaling pathways in cells with TMEM176B overexpression and silencing. Silencing TMEM176B or inhibiting it with a therapeutic antibody impaired cell proliferation, while overexpression increased proliferation in vitro. Syngeneic and xenograft tumor studies revealed the attenuated growth of tumors with TMEM176B gene silencing compared with controls. We found that the AKT/mTOR signaling pathway was activated or repressed in cells overexpressing or silenced for TMEM176B, respectively. Overall, our results suggest that TMEM176B expression in breast cancer cells regulates key signaling pathways and genes that contribute to cancer cell growth and progression, and is a potential target for therapeutic antibodies.

Multi-omics approaches reveal a link between the MS4A gene loci, TREM2, and microglia function.

Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been associated with Alzheimer's disease (AD). TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may reveal new pathological mechanisms and lead to the identification of therapeutic targets. We recently identified common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region that were associated with CSF sTREM2 concentrations. One variant (rs1582763) was associated with increased CSF sTREM2 and reduced AD risk, while a second variant (rs6591561) was associated with reduced CSF sTREM2 and increased AD risk. Using human induced pluripotent stem cell-derived microglia, we found that MS4A4A and TREM2 colocalize on lipid rafts at the plasma membrane. Here, we sought to define the molecular mechanism by which variants in the MS4A gene region impact sTREM2, microglia function and AD risk. To define the functional effects of MS4A variants, we used genotype and bulk RNAseq data from 579 human brain samples. We then evaluated microglia specific effects using single nuclei RNAseq data obtained from 64 human brains. Leveraging genotypic and transcriptomic data in human brain tissue, we found that rs1582763 and rs6591561 alter distinct molecular pathways. Rs1582763, which confers AD resilience, impacts pathways associated with cholesterol metabolism, while rs6591561, which confers AD risk, impacts pathways associated with chemokine regulation. Using single nuclei RNAseq data in human brain tissue, we found that these variants are associated with MS4A4A expression within microglia. Additionally, these variants modify cellular proportions of a functionally distinct microglia population. Together, these findings begin to provide a mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 may be involved in AD pathogenesis not only in TREM2 risk-variant carriers but also in those with sporadic disease.

MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia.

Alimentary toxic aleukia (ATA) is correlated with consuming grains contaminated by Fusarium species, particularly T-2 toxin, which causes serious hurt to human and animal health, chiefly in disorders of the haematopoietic system. However, the mechanism of haematopoietic dysfunction induced by T-2 toxin and the possible target pathway for the treatment of T-2 toxin-induced haematopoietic disorder of ATA remains unclear. In this study, genomes and proteomics were used for the first time to investigate the key differential genes and proteins that inhibit erythroid differentiation of K562 cells caused by T-2 toxin, and it was found that heat shock protein 27 (HSP27) and membrane-spanning 4-domains, subfamily A, member 3 (MS4A3) may play an important role in erythroid differentiation. Meanwhile, MS4A3 interference can inhibit the occurrence of erythroid differentiation of K562 cells and promote the phosphorylation of HSP27. Moreover, the binding of HSP27 to MS4A3 in natural state can activate the phosphorylation site of HSP27 (Ser-83), while T-2 toxin can abolish the activation of phosphorylation site by inhibiting the expression of MS4A3. These findings for the first time demonstrated that the MS4A3-HSP27 pathway may function an efficient therapeutic target pathway for treating T-2 toxin elicited haematopoietic disorders of ATA.

Trans-Ethnic Meta-Analysis of Interactions Between Genetics and Early-Life Socioeconomic Context on Memory Performance and Decline in Older Americans.

Later-life cognitive function is influenced by genetics as well as early- and later-life socioeconomic context. However, few studies have examined the interaction between genetics and early childhood factors. Using gene-based tests (interaction sequence kernel association test [iSKAT]/iSKAT optimal unified test), we examined whether common and/or rare exonic variants in 39 gene regions previously associated with cognitive performance, dementia, and related traits had an interaction with childhood socioeconomic context (parental education and financial strain) on memory performance or decline in European ancestry (EA, N = 10 468) and African ancestry (AA, N = 2 252) participants from the Health and Retirement Study. Of the 39 genes, 22 in EA and 19 in AA had nominally significant interactions with at least one childhood socioeconomic measure on memory performance and/or decline; however, all but one (father's education by solute carrier family 24 member 4 [SLC24A4] in AA) were not significant after multiple testing correction (false discovery rate [FDR] < .05). In trans-ethnic meta-analysis, 2 genes interacted with childhood socioeconomic context (FDR < .05): mother's education by membrane-spanning 4-domains A4A (MS4A4A) on memory performance, and father's education by SLC24A4 on memory decline. Both interactions remained significant (p < .05) after adjusting for respondent's own educational attainment, apolipoprotein-ε4 allele (APOE ε4) status, lifestyle factors, body mass index, and comorbidities. For both interactions in EA and AA, the genetic effect was stronger in participants with low parental education. Examination of common and rare variants in genes discovered through genome-wide association studies shows that childhood context may interact with key gene regions to jointly impact later-life memory function and decline. Genetic effects may be more salient for those with lower childhood socioeconomic status.

A Likelihood Ratio Test for Gene-Environment Interaction Based on the Trend Effect of Genotype Under an Additive Risk Model Using the Gene-Environment Independence Assumption.

Several statistical methods have been proposed for testing gene-environment (G-E) interactions under additive risk models using data from genome-wide association studies. However, these approaches have strong assumptions from underlying genetic models, such as dominant or recessive effects that are known to be less robust when the true genetic model is unknown. We aimed to develop a robust trend test employing a likelihood ratio test for detecting G-E interaction under an additive risk model, while incorporating the G-E independence assumption to increase power. We used a constrained likelihood to impose 2 sets of constraints for: 1) the linear trend effect of genotype and 2) the additive joint effects of gene and environment. To incorporate the G-E independence assumption, a retrospective likelihood was used versus a standard prospective likelihood. Numerical investigation suggests that the proposed tests are more powerful than tests assuming dominant, recessive, or general models under various parameter settings and under both likelihoods. Incorporation of the independence assumption enhances efficiency by 2.5-fold. We applied the proposed methods to examine the gene-smoking interaction for lung cancer and gene-apolipoprotein E $\varepsilon$4 interaction for Alzheimer disease, which identified 2 interactions between apolipoprotein E $\varepsilon$4 and loci membrane-spanning 4-domains subfamily A (MS4A) and bridging integrator 1 (BIN1) genes at genome-wide significance that were replicated using independent data.

Microglia-Related Gene Triggering Receptor Expressed in Myeloid Cells 2 (TREM2) Is Upregulated in the Substantia Nigra of Progressive Supranuclear Palsy.

The role of the microglia-related gene triggering receptor expressed in myeloid cells 2 (TREM2) in primary tauopathies, such as progressive supranuclear palsy (PSP), still remains unclear. The objective of this study was to profile overall and transcript-specific TREM2 expression levels in the substantia nigra (SN) of PSP patients and controls. SN samples from neuropathologically confirmed PSP cases (n = 24) and controls (n = 14) were used to measure TREM2 and TREM2-modulating gene Membrane-spanning 4-domains subfamily A member 4A (MS4A4A) mRNA levels by real-time quantitative polymerase chain reaction. Correlation with hyperphosphorylated tau protein burden was assessed. Overall TREM2 and each of the 3 TREM2 transcripts mRNA levels were significantly increased in the SN of PSP cases versus controls. TREM2 mRNA levels positively correlated with hyperphosphorylated tau burden in SN, specifically in neurons. The MS4A4A gene was also upregulated in PSP patients versus controls. These results add evidence to the involvement of microglia in the disease process of PSP. These findings support the idea that different tauopathies may share common patterns of deregulation in innate immune molecular pathways. © 2020 International Parkinson and Movement Disorder Society.

Long Noncoding RNA COPDA1 Promotes Airway Smooth Muscle Cell Proliferation in Chronic Obstructive Pulmonary Disease.

Abnormal expression of long noncoding RNAs (lncRNAs) has been confirmed to be associated with many diseases, including chronic obstructive pulmonary disease (COPD). To gain better understanding of the mechanism of COPD, we investigated the lncRNA and mRNA profiles in the lung tissue of patients with COPD. According to the analysis, one of the significantly different lncRNAs, COPDA1, might participate in the occurrence and development of COPD. Lung tissues were collected from nonsmokers, smokers, or smokers with COPD for RNA sequencing. Bioinformatic analysis and cell experiments were used to define the function of COPDA1, and the effects of COPDA1 on intracellular Ca2+ concentration and cell proliferation were examined after knockdown or overexpression of COPDA1. A number of variations of lncRNAs were found in the comparison of nonsmokers, smokers, and smokers with COPD. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analyses indicated that smoking was involved in the activation of cytokines and the cell cycle, which is associated with COPD. According to the lncRNA-mRNA-coexpressing network and enrichment analysis, COPDAz1 and one of its target genes, MS4A1 (membrane-spanning 4-domains family, subfamily A) were investigated, and we discovered that the expression of MS4A1 was closely associated with lncRNA COPDA1 expression in human bronchial smooth muscle cells (HBSMCs). Further study showed that lncRNA COPDA1 upregulated the expression of MS4A1 to increase store-operated calcium entry in the HBSMCs, resulting in the promotion of the proliferation of smooth muscle cells as well as of airway remodeling. COPDA1 might be involved in the regulation of certain signaling pathways in COPD, might promote the proliferation of HBSMCs, and might also be involved in facilitating airway remodeling.

The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer's disease risk.

Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been associated with Alzheimer's disease (AD). TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may reveal new pathological mechanisms and lead to the identification of therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 obtained from the Alzheimer's Disease Neuroimaging Initiative. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with CSF sTREM2 concentrations (rs1582763; P = 1.15 × 10-15); this was replicated in independent datasets. The variants associated with increased CSF sTREM2 concentrations were associated with reduced AD risk and delayed age at onset of disease. The single-nucleotide polymorphism rs1582763 modified expression of the MS4A4A and MS4A6A genes in multiple tissues, suggesting that one or both of these genes are important for modulating sTREM2 production. Using human macrophages as a proxy for microglia, we found that MS4A4A and TREM2 colocalized on lipid rafts at the plasma membrane, that sTREM2 increased with MS4A4A overexpression, and that silencing of MS4A4A reduced sTREM2 production. These genetic, molecular, and cellular findings suggest that MS4A4A modulates sTREM2. These findings also provide a mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 may be involved in AD pathogenesis not only in TREM2 risk-variant carriers but also in those with sporadic disease.

Relationship among MS4A8 expression, its variants, and the immune response in a porcine model of Salmonella

Salmonella colonization often establishes carrier status in infected animals, which decreases their performance. Salmonella-carrying pigs shed large amounts of bacteria in their feces, and thus they have a negative economic impact on the swine industry. The MS4A8 gene (membrane-spanning 4-domains A8) was significantly activated, by up to 119-fold, in peripheral blood after Salmonella inoculation of pigs. The present study analyzed the correlation of peripheral blood expression level and a genetic variant of porcine MS4A8 with Salmonella-infection traits. The result indicated that MS4A8 expression levels correlated significantly with Salmonella shedding counts. Both the expression of MS4A8 and fecal shedding counts correlated with leukocytes, lymphocytes, monocytes, segmented neutrophils, and banded neutrophils. A novel single nucleotide polymorphism of porcine MS4A8 (nonsynonymous, Val &gt; Ala) was associated with Salmonella shedding counts and average daily gain (ADG) of body weight. The TT genotype had higher fecal shedding counts, leukocyte counts, and lymphocyte counts than the TC and CC genotypes. The CC genotype had higher level of ADG than the TC and TT genotype (p &lt; 0.05). Those results indicated that MS4A8 is intriguing and could be used as a prospective genetic marker for Salmonella susceptibility.

New genetic players in late-onset Alzheimer's disease: Findings of genome-wide association studies.

Late-onset Alzheimer's disease (LOAD) or sporadic AD is the most common form of AD. The precise pathogenetic changes that trigger the development of AD remain largely unknown. Large-scale genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms in multiple genes which are associated with AD; most notably, these are ABCA7, bridging integrator 1(B1N1), triggering receptor expressed on myeloid cells 2 (TREM2), CD33, clusterin (CLU), complement receptor 1 (CRI), ephrin type-A receptor 1 (EPHA1), membrane-spanning 4-domains, subfamily A (MS4A) and phosphatidylinositol binding clathrin assembly protein (PICALM) genes. The proteins coded by the candidate genes participate in a variety of cellular processes such as oxidative balance, protein metabolism, cholesterol metabolism and synaptic function. This review summarizes the major gene loci affecting LOAD identified by large GWASs. Tentative mechanisms have also been elaborated in various studies by which the proteins coded by these genes may exert a role in AD pathogenesis have also been elaborated. The review suggests that these may together affect LOAD pathogenesis in a complementary fashion.

Identification of MS4A3 as a reliable marker for early myeloid differentiation in human hematopoiesis

Information of myeloid lineage-related antigen on hematopoietic stem/progenitor cells (HSPCs) is important to clarify the mechanisms regulating hematopoiesis, as well as for the diagnosis and treatment of myeloid malignancies. We previously reported that special AT-rich sequence binding protein 1 (SATB1), a global chromatin organizer, promotes lymphoid differentiation from HSPCs. To search a novel cell surface molecule discriminating early myeloid and lymphoid differentiation, we performed microarray analyses comparing SATB1-overexpressed HSPCs with mock-transduced HSPCs. The results drew our attention to membrane-spanning 4-domains, subfamily A, member 3 (Ms4a3) as the most downregulated molecule in HSPCs with forced overexpression of SATB1. Ms4a3 expression was undetectable in hematopoietic stem cells, but showed a concomitant increase with progressive myeloid differentiation, whereas not only lymphoid but also megakaryocytic-erythrocytic progenitors were entirely devoid of Ms4a3 expression. Further analysis revealed that a subset of CD34+CD38+CD33+ progenitor population in human adult bone marrow expressed MS4A3, and those MS4A3+ progenitors only produced granulocyte/macrophage colonies, losing erythroid colony- and mixed colony-forming capacity. These results suggest that cell surface expression of MS4A3 is useful to distinguish granulocyte/macrophage lineage-committed progenitors from other lineage-related ones in early human hematopoiesis. In conclusion, MS4A3 is useful to monitor early stage of myeloid differentiation in human hematopoiesis.

A hypermorphic antioxidant response element is associated with increased MS4A6A expression and Alzheimer's disease

Late onset Alzheimer's disease (AD) is a multifactorial disorder, with AD risk influenced by both environmental and genetic factors. Recent genome-wide association studies (GWAS) have identified genetic loci associated with increased risk of developing AD. The MS4A (membrane-spanning 4-domains subfamily A) gene cluster is one of the most significant loci associated with AD risk, and MS4A6A expression is correlated with AD pathology. We identified a single nucleotide polymorphism, rs667897, at the MS4A locus that creates an antioxidant response element and links MS4A6A expression to the stress responsive Cap-n-Collar (CNC) transcription factors NRF1 (encoded by NFE2L1) and NRF2 (encoded by NFE2L2). The risk allele of rs667897 generates a strong CNC binding sequence that is activated by proteostatic stress in an NRF1-dependent manner, and is associated with increased expression of the gene MS4A6A. Together, these findings suggest that the cytoprotective CNC regulatory network aberrantly activates MS4A6A expression and increases AD risk in a subset of the population.

Morphologic, phenotypic, and transcriptomic characterization of classically and alternatively activated canine blood-derived macrophages in vitro.

Macrophages are a heterogeneous cell population playing a pivotal role in tissue homeostasis and inflammation, and their phenotype strongly depends on the micromilieu. Despite its increasing importance as a translational animal model for human diseases, there is a considerable gap of knowledge with respect to macrophage polarization in dogs. The present study comprehensively investigated the morphologic, phenotypic, and transcriptomic characteristics of unstimulated (M0), M1- (GM-CSF, LPS, IFNγ-stimulated) and M2- (M-CSF, IL-4-stimulated)-polarized canine blood-derived macrophages in vitro. Scanning electron microscopy revealed distinct morphologies of polarized macrophages with formation of multinucleated cells in M2-macrophages, while immunofluorescence employing literature-based prototype-antibodies against CD16, CD32, iNOS, MHC class II (M1-markers), CD163, CD206, and arginase-1 (M2-markers) demonstrated that only CD206 was able to discriminate M2-macrophages from both other phenotypes, highlighting this molecule as a promising marker for canine M2-macrophages. Global microarray analysis revealed profound changes in the transcriptome of polarized canine macrophages. Functional analysis pointed out that M1-polarization was associated with biological processes such as “respiratory burst”, whereas M2-polarization was associated with processes such as “mitosis”. Literature-based marker gene selection revealed only minor overlaps in the gene sets of the dog compared to prototype markers of murine and human macrophages. Biomarker selection using supervised clustering suggested latexin (LXN) and membrane-spanning 4-domains, subfamily A, member 2 (MS4A2) to be the most powerful predicting biomarkers for canine M1- and M2-macrophages, respectively. Immunofluorescence for both markers demonstrated expression of both proteins by macrophages in vitro but failed to reveal differences between canine M1 and M2-macrophages. The present study provides a solid basis for future studies upon the role of macrophage polarization in spontaneous diseases of the dog, a species that has emerging importance for translational research.

Shifts in the Gut Microbiota Composition Due to Depleted Bone Marrow Beta Adrenergic Signaling Are Associated with Suppressed Inflammatory Transcriptional Networks in the Mouse Colon.

The brain-gut axis plays a critical role in the regulation of different diseases, many of which are characterized by sympathetic dysregulation. However, a direct link between sympathetic dysregulation and gut dysbiosis remains to be illustrated. Bone marrow (BM)-derived immune cells continuously interact with the gut microbiota to maintain homeostasis in the host. Their function is largely dependent upon the sympathetic nervous system acting via adrenergic receptors present on the BM immune cells. In this study, we utilized a novel chimera mouse that lacks the expression of BM beta1/2 adrenergic receptors (b1/2-ARs) to investigate the role of the sympathetic drive to the BM in gut and microbiota homeostasis. Fecal analyses demonstrated a shift from a dominance of Firmicutes to Bacteroidetes phylum in the b1/2-ARs KO chimera, resulting in a reduction in Firmicutes/Bacteroidetes ratio. Meanwhile, a significant reduction in Proteobacteria phylum was determined. No changes in the abundance of acetate-, butyrate-, and lactate-producing bacteria, and colon pathology were observed in the b1/2-ARs KO chimera. Transcriptomic profiling in colon identified Killer Cell Lectin-Like Receptor Subfamily D, Member 1 (Klrd1), Membrane-Spanning 4-Domains Subfamily A Member 4A (Ms4a4b), and Casein Kinase 2 Alpha Prime Polypeptide (Csnk2a2) as main transcripts associated with the microbiota shifts in the b1/2-ARs KO chimera. Suppression of leukocyte-related transcriptome networks (i.e., function, differentiation, migration), classical compliment pathway, and networks associated with intestinal function, barrier integrity, and excretion was also observed in the colon of the KO chimera. Moreover, reduced expression of transcriptional networks related to intestinal diseases (i.e., ileitis, enteritis, inflammatory lesions, and stress) was noted. The observed suppressed transcriptome networks were associated with a reduction in NK cells, macrophages, and CD4+ T cells in the b1/2-ARs KO chimera colon. Thus, sympathetic regulation of BM-derived immune cells plays a significant role in modifying inflammatory networks in the colon and the gut microbiota composition. To our knowledge, this study is the first to suggest a key role of BM b1/2-ARs signaling in host-microbiota interactions, and reveals specific molecular mechanisms that may lead to generation of novel anti-inflammatory treatments for many immune and autonomic diseases as well as gut dysbiosis across the board.

MS4A6A genotypes are associated with the atrophy rates of Alzheimer's disease related brain structures.

Membrane-spanning 4-domains, subfamily A, member 6A (MS4A6A) has been identified as susceptibility loci of Alzheimer's disease (AD) by several recent genome-wide association studies (GWAS), whereas little is known about the potential roles of these variants in the brain structure and function of AD. In this study, we included a total of 812 individuals from the Alzheimer's disease Neuroimaging Initiative (ADNI) database. Using multiple linear regression models, we found MS4A6A genotypes were strongly related to atrophy rate of left middle temporal (rs610932: Pc = 0.017, rs7232: Pc = 0.022), precuneus (rs610932: Pc = 0.015) and entorhinal (rs610932, Pc = 0.022) on MRI in the entire group. In the subgroup analysis, MS4A6A SNPs were significantly accerlated the percentage of volume loss of middle temporal, precuneus and entorhinal, especially in the MCI subgroup. These findings reveal that MS4A6A genotypes affect AD specific brain structures which supported the possible role of MS4A6A polymorphisms in influencing AD-related neuroimaging phenotypes.

Assessment of Radiation Induced Therapeutic Effect and Cytotoxicity in Cancer Patients Based on Transcriptomic Profiling.

Toxicity induced by radiation therapy is a curse for cancer patients undergoing treatment. It is imperative to understand and define an ideal condition where the positive effects notably outweigh the negative. We used a microarray meta-analysis approach to measure global gene-expression before and after radiation exposure. Bioinformatic tools were used for pathways, network, gene ontology and toxicity related studies. We found 429 differentially expressed genes at fold change >2 and p-value <0.05. The most significantly upregulated genes were synuclein alpha (SNCA), carbonic anhydrase I (CA1), X-linked Kx blood group (XK), glycophorin A and B (GYPA and GYPB), and hemogen (HEMGN), while downregulated ones were membrane-spanning 4-domains, subfamily A member 1 (MS4A1), immunoglobulin heavy constant mu (IGHM), chemokine (C-C motif) receptor 7 (CCR7), BTB and CNC homology 1 transcription factor 2 (BACH2), and B-cell CLL/lymphoma 11B (BCL11B). Pathway analysis revealed calcium-induced T lymphocyte apoptosis and the role of nuclear factor of activated T-cells (NFAT) in regulation of the immune response as the most inhibited pathways, while apoptosis signaling was significantly activated. Most of the normal biofunctions were significantly decreased while cell death and survival process were activated. Gene ontology enrichment analysis revealed the immune system process as the most overrepresented group under the biological process category. Toxicity function analysis identified liver, kidney and heart to be the most affected organs during and after radiation therapy. The identified biomarkers and alterations in molecular pathways induced by radiation therapy should be further investigated to reduce the cytotoxicity and development of fatigue.

The role of immunity and neuroinflammation in genetic predisposition and pathogenesis of Alzheimer’s disease

AbstractAlzheimer's disease is an important public concern with rising prevalence across the globe. While many therapeutic approaches for Alzheimer's disease have been developed, there are currently no validated disease-modifying treatments. Thus, in order to develop novel treatment strategies, there is a significant need to progress our understanding of the pathogenesis of Alzheimer's disease. Several large genome-wide association studies and whole genome and exome sequencing studies have identified novel genes associated with late-onset Alzheimer's disease. Interestingly, many of the genes are associated with inflammation and the immune system, including complement receptor 1, clusterin, CD33, EPH receptor A1, membrane-spanning 4-domains subfamily A, ATP-binding cassette sub-family A member 7, major histocompatibility complex class II, inositol polyphosphate-5-phosphatase, myocyte enhancer factor 2C, and triggering receptor expressed on myeloid cells 2. The pathogenetic contributions of immune reaction and neuroinflammation in Alzheimer's disease have been regarded largely as part of amyloid cascade hypothesis. The neurotoxic amyloid-β (Aβ) induces activation of immune cells, such as microglia, astrocytes, perivascular macrophages and lymphocytes and decreased capability of clearing Aβ by immune system and chronic inflammation caused by activated immune cells aggravate neuronal damage and eventually Alzheimer's disease. But the precise mechanism and hereditary impact on such process is largely unknown. The current findings in genetic studies suggest that the immunological mechanisms of Alzheimer's disease may extend beyond passive reaction of Aβ, including the development of Alzheimer's disease such as time of onset and rate of progression. In this article, we aimed to review the mechanisms of immune reaction and neuroinflammation in Alzheimer's disease, with an emphasis on the function of genes known to be associated with a risk of Alzheimer's disease in terms of neuroinflammation and immune function.