Identification of a unique TGF-?-dependent molecular and functional signature in microglia.
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ABSTRACT:
SUBMITTER: Butovsky O
PROVIDER: S-EPMC4066672 | biostudies-literature | 2014 Jan
REPOSITORIES: biostudies-literature
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Project description:Microglia are myeloid cells of the central nervous system (CNS) that participate both in normal CNS function and disease. We investigated the molecular signature of microglia and identified 239 genes and 8 microRNAs that were uniquely or highly expressed in microglia vs. myeloid and other immune cells. Out of 239 genes, 106 were enriched in microglia as compared to astrocytes, oligodendrocytes and neurons. This microglia signature was not observed in microglial lines or in monocytes recruited to the CNS and was also observed in human microglia. Based on this signature, we found a crucial role for TGF-β in microglial biology that included: 1) the requirement of TGF-β for the in vitro development of microglia that express the microglial molecular signature characteristic of adult microglia; and 2) the absence of microglia in CNS TGF-β1 deficient mice. Our results identify a unique microglial signature that is dependent on TGF-β signaling which provides insights into microglial biology and the possibility of targeting microglia for the treatment of CNS disease.
2013-07-08 | GSE48579 | GEO
Project description:BACKGROUND:Lysosomal storage diseases (LSD) are a large family of inherited disorders characterized by abnormal endolysosomal accumulation of cellular material due to catabolic enzyme and transporter deficiencies. Depending on the affected metabolic pathway, LSD manifest with somatic or central nervous system (CNS) signs and symptoms. Neuroinflammation is a hallmark feature of LSD with CNS involvement such as mucolipidosis type IV, but not of others like Fabry disease. METHODS:We investigated the properties of microglia from LSD with and without major CNS involvement in 2-month-old mucolipidosis type IV (Mcoln1-/-) and Fabry disease (Glay/-) mice, respectively, by using a combination of flow cytometric, RNA sequencing, biochemical, in vitro and immunofluorescence analyses. RESULTS:We characterized microglia activation and transcriptome from mucolipidosis type IV and Fabry disease mice to determine if impaired lysosomal function is sufficient to prime these brain-resident immune cells. Consistent with the neurological pathology observed in mucolipidosis type IV, Mcoln1-/- microglia demonstrated an activation profile with a mixed neuroprotective/neurotoxic expression pattern similar to the one we previously observed in Niemann-Pick disease, type C1, another LSD with significant CNS involvement. In contrast, the Fabry disease microglia transcriptome revealed minimal alterations, consistent with the relative lack of CNS symptoms in this disease. The changes observed in Mcoln1-/- microglia showed significant overlap with alterations previously reported for other common neuroinflammatory disorders including Alzheimer's, Parkinson's, and Huntington's diseases. Indeed, our comparison of microglia transcriptomes from Alzheimer's disease, amyotrophic lateral sclerosis, Niemann-Pick disease, type C1 and mucolipidosis type IV mouse models showed an enrichment in "disease-associated microglia" pattern among these diseases. CONCLUSIONS:The similarities in microglial transcriptomes and features of neuroinflammation and microglial activation in rare monogenic disorders where the primary metabolic disturbance is known may provide novel insights into the immunopathogenesis of other more common neuroinflammatory disorders. TRIAL REGISTRATION:ClinicalTrials.gov, NCT01067742, registered on February 12, 2010.
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Project description:: The regulation of microglial cell phenotype is a potential therapeutic intervention in neurodegenerative disease. Previously, we reported that transforming growth factor-β (TGF-β) levels in mesenchymal stromal cells (MSCs) could be used as potential biological markers to predict the effectiveness of autologous MSC therapy in patients with amyotrophic lateral sclerosis. However, the underlying mechanism of TGF-β in MSCs was not fully elucidated in determining the functional properties of microglia. In this study, we aimed to clarify the role of TGF-β that is involved in MSC effectiveness, especially focusing on microglia functional properties that play a pivotal role in neuroinflammation. We found that MSC-conditioned media (MSC-CM) inhibited proinflammatory cytokine expression, restored alternative activated microglia phenotype markers (fractalkine receptor, mannose receptor, CD200 receptor), and enhanced phagocytosis in lipopolysaccharide (LPS)-stimulated microglia. In addition, TGF-β in MSC-CM played a major role in these effects by inhibiting the nuclear factor-κB pathway and restoring the TGF-β pathway in LPS-stimulated microglia. Recombinant TGF-β also induced similar effects to MSC-CM in LPS-stimulated microglia. Therefore, we propose that MSCs can modulate the functional properties of microglia via TGF-β secretion, switching them from a classically activated phenotype to an inflammation-resolving phenotype. The latter role may be associated with the inhibition of neuroinflammatory processes in neurodegenerative disorders.SignificanceThe results of this study showed that microglia functional properties may be modulated depending on the composition and quantity of mesenchymal stromal cell (MSC)-secreting factors. Transforming growth factor (TGF)-β is proposed as a modulator of microglia functional properties among MSC-secreting factors, and this study aligns with a previous clinical study by these same authors. TGF-β releasing capacity could be an important factor enhancing the therapeutic efficacy of MSCs in clinical trials.
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Project description:The activation and proliferation of microglia is characteristic of the early stages of brain pathologies. In this study, we aimed to identify a factor that promotes microglial activation and proliferation and examined the in vitro effects on these processes. We cultured microglial cell lines, EOC 2 and SIM-A9, with various growth factors and evaluated cell proliferation, death, and viability. The results showed that only transforming growth factor beta (TGF-β) caused an increase in the in vitro proliferation of both microglial cell lines. It has been reported that colony-stimulating factor 1 promotes the proliferation of microglia, while TGF-β promotes both proliferation and inhibition of cell death of microglia. However, upon comparing the most effective doses of both (assessed from the proliferation assay), we identified no statistically significant difference between the two factors in terms of cell death; thus, both have a proliferative effect on microglial cells. In addition, a TGF-β receptor 1 inhibitor, galunisertib, caused marked inhibition of proliferation in a dose-dependent manner, indicating that inhibition of TGF-β signalling reduces the proliferation of microglia. Therefore, galunisertib may represent a promising therapeutic agent for the treatment of neurodegenerative diseases via inhibition of nerve injury-induced microglial proliferation, which may result in reduced inflammatory and neuropathic and cancer pain.
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Project description:The transforming growth factor-βs (TGF-βs) are multifunctional cytokines capable of regulating a wide range of cellular behaviors and play a key role in maintaining the homeostasis of the immune system. The TGF-β subfamily, which is only present in deuterostomes, expands from a single gene in invertebrates to multiple members in jawed vertebrates. However, the evolutionary processes of the TGF-β subfamily in vertebrates still lack sufficient elucidation. In this study, the TGF-β homologs are identified at the genome-wide level in the reissner lamprey (Lethenteron reissneri), the sea lamprey (Petromyzon marinus), and the Japanese lamprey (Lampetra japonica), which are the extant representatives of jawless vertebrates with a history of more than 350 million years. The molecular evolutionary analyses reveal that the lamprey TGF-β subfamily contains two members representing ancestors of TGF-β2 and 3 in vertebrates, respectively, but TGF-β1 is absent. The transcriptional expression patterns show that the lamprey TGF-β2 may play a central regulatory role in the innate immune response of the lamprey since it exhibits a more rapid and significant upregulation of expression than TGF-β3 during lipopolysaccharide stimuli. The incorporation of BrdU assay reveals that the lamprey TGF-β2 recombinant protein exerts the bipolar regulation on the proliferation of the supraneural myeloid body cells (SMB cells) in the quiescent and LPS-activated state, while plays an inhibitory role in the proliferation of quiescent and activated leukocytes in lampreys. Furthermore, caspase-3/7 activity analysis indicates that the lamprey TGF-β2 protects SMB cells from apoptosis after serum deprivation, in contrast to promoting apoptosis of leukocytes. Our composite results offer valuable clues to the origin and evolution of the TGF-β subfamily and imply that TGF-βs are among the most ancestral immune regulators in vertebrates.
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Project description:Neuronal activity is closely influenced by glia, especially microglia which are the resident immune cells in the central nervous system (CNS). Microglia in medicinal leech are the only cells able to migrate to the injury site within the 24 hours post-lesion. The microglia-neuron interactions constitute an important mechanism as there is neither astrocyte nor oligodendrocyte in the leech CNS. Given that axonal sprouting is impaired when microglia recruitment is inhibited, the crosstalk between microglia and neurons plays a crucial role in neuroprotection. The present results show that neurons and microglia both use ALK4/5 (a type of TGF-β receptor) signaling in order to maintain mutual exchanges in an adult brain following an axonal injury. Indeed, a TGF-β family member (nGDF) is immediately released by injured axons contributing to the early recruitment of ALK4/5+ microglia to the lesion site. Surprisingly, within the following hours, nGDF from microglia activates ALK4/5+ neurons to maintain a later microglia accumulation in lesion. Taken together, the results demonstrate that ALK4/5 signaling is essential throughout the response to the lesion in the leech CNS and gives a new insight in the understanding of this pathway. This latter is an important signal contributing to a correct sequential mobilization over time of microglia recruitment leading to axon regeneration.
| S-EPMC6499822 | biostudies-literature
Project description:BACKGROUND & AIMS:A generalized human pacemaking syndrome, chronic atrial and intestinal dysrhythmia (CAID) (OMIM 616201), is caused by a homozygous SGO1 mutation (K23E), leading to chronic intestinal pseudo-obstruction and arrhythmias. Because CAID patients do not show phenotypes consistent with perturbation of known roles of SGO1, we hypothesized that noncanonical roles of SGO1 drive the clinical manifestations observed. METHODS:To identify a molecular signature for CAID syndrome, we achieved unbiased screens in cell lines and gut tissues from CAID patients vs wild-type controls. We performed RNA sequencing along with stable isotope labeling with amino acids in cell culture. In addition, we determined the genome-wide DNA methylation and chromatin accessibility signatures using reduced representative bisulfite sequencing and assay for transposase-accessible chromatin with high-throughput sequencing. Functional studies included patch-clamp, quantitation of transforming growth factor-β (TGF-β) signaling, and immunohistochemistry in CAID patient gut biopsy specimens. RESULTS:Proteome and transcriptome studies converge on cell-cycle regulation, cardiac conduction, and smooth muscle regulation as drivers of CAID syndrome. Specifically, the inward rectifier current, an important regulator of cellular function, was disrupted. Immunohistochemistry confirmed overexpression of Budding Uninhibited By Benzimidazoles 1 (BUB1) in patients, implicating the TGF-β pathway in CAID pathogenesis. Canonical TGF-β signaling was up-regulated and uncoupled from noncanonical signaling in CAID patients. Reduced representative bisulfite sequencing and assay for transposase-accessible chromatin with high-throughput sequencing experiments showed significant changes of chromatin states in CAID, pointing to epigenetic regulation as a possible pathologic mechanism. CONCLUSIONS:Our findings point to impaired inward rectifier potassium current, dysregulation of canonical TGF-β signaling, and epigenetic regulation as potential drivers of intestinal and cardiac manifestations of CAID syndrome. Transcript profiling and genomics data are as follows: repository URL: https://www.ncbi.nlm.nih.gov/geo; SuperSeries GSE110612 was composed of the following subseries: GSE110309, GSE110576, and GSE110601.
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Project description:MicroRNAs (miRNA) have emerged as an important new class of modulators of gene expression. In this study we investigated miRNA that are differentially expressed in lupus nephritis. Microarray technology was used to investigate differentially expressed miRNA in peripheral blood mononuclear cells (PBMCs) and Epstein-Barr Virus (EBV)-transformed cell lines obtained from lupus nephritis affected patients and unaffected controls. TaqMan-based stem-loop real-time polymerase chain reaction was used for validation. Microarray analysis of miRNA expressed in both African American (AA) and European American (EA) derived lupus nephritis samples revealed 29 and 50 differentially expressed miRNA, respectively, of 850 tested. There were 18 miRNA that were differentially expressed in both racial groups. When samples from both racial groups and different specimen types were considered, there were 5 primary miRNA that were differentially expressed. We have identified 5 miRNA; hsa-miR-371-5P, hsa-miR-423-5P, hsa-miR-638, hsa-miR-1224-3P and hsa-miR-663 that were differentially expressed in lupus nephritis across different racial groups and all specimen types tested. Hsa-miR-371-5P, hsa-miR-1224-3P and hsa-miR-423-5P, are reported here for the first time to be associated with lupus nephritis. Our work establishes EBV-transformed B cell lines as a useful model for the discovery of miRNA as biomarkers for SLE. Based on these findings, we postulate that these differentially expressed miRNA may be potential novel biomarkers for SLE as well as help elucidate pathogenic mechanisms of lupus nephritis. The investigation of miRNA profiles in SLE may lead to the discovery and development of novel methods to diagnosis, treat and prevent SLE.
| S-EPMC2867940 | biostudies-literature
Project description:BackgroundTransforming growth factor (TGF)-β signaling functions importantly in regulating tumor microenvironment (TME). This study developed a prognostic gene signature based on TGF-β signaling-related genes for predicting clinical outcome of patients with lung adenocarcinoma (LUAD).MethodsTGF-β signaling-related genes came from The Molecular Signature Database (MSigDB). LUAD prognosis-related genes were screened from all the genes involved in TGF-β signaling using least absolute shrinkage and selection operator (LASSO) Cox regression analysis and then used to establish a risk score model for LUAD. ESTIMATE and CIBERSORT analyzed infiltration of immune cells in TME. Immunotherapy response was analyzed by the TIDE algorithm.ResultsA LUAD prognostic 5-gene signature was developed based on 54 TGF-β signaling-related genes. Prognosis of high-risk patients was significantly worse than low-risk patients. Both internal validation and external dataset validation confirmed a high precision of the risk model in predicting the clinical outcomes of LUAD patients. Multivariate Cox analysis demonstrated the model independence in OS prediction of LUAD. The risk model was significantly related to the infiltration of 9 kinds of immune cells, matrix, and immune components in TME. Low-risk patients tended to respond more actively to anti-PD-1 treatment, while high-risk patients were more sensitive to chemotherapy and targeted therapy.ConclusionsThe 5-gene signature based on TGF-β signaling-related genes showed potential for LUAD management.
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Project description:The TREM2-DAP12 receptor complex sustains microglia functions. Heterozygous hypofunctional TREM2 variants impair microglia, accelerating late-onset Alzheimer's disease. Homozygous inactivating variants of TREM2 or TYROBP-encoding DAP12 cause Nasu-Hakola disease (NHD), an early-onset dementia characterized by cerebral atrophy, myelin loss and gliosis. Mechanisms underpinning NHD are unknown. Here, single-nucleus RNA-sequencing analysis of brain specimens from DAP12-deficient NHD individuals revealed a unique microglia signature indicating heightened RUNX1, STAT3 and transforming growth factor-β signaling pathways that mediate repair responses to injuries. This profile correlated with a wound healing signature in astrocytes and impaired myelination in oligodendrocytes, while pericyte profiles indicated vascular abnormalities. Conversely, single-nuclei signatures in mice lacking DAP12 signaling reflected very mild microglial defects that did not recapitulate NHD. We envision that DAP12 signaling in microglia attenuates wound healing pathways that, if left unchecked, interfere with microglial physiological functions, causing pathology in human. The identification of a dysregulated NHD microglia signature sparks potential therapeutic strategies aimed at resetting microglia signaling pathways.
| S-EPMC9992145 | biostudies-literature