Salt augments macrophage-driven host defense in the skin
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina HiSeq 2000
ORGANISM(S): Mus musculus
SUBMITTER: Matthias Gebhardt
PROVIDER: E-MTAB-3343 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Inflammation and infection can trigger local tissue Na+-accumulation. This Na+-rich environment boosts pro-inflammatory activation of monocyte/macrophage-like cells (MΦ) and their antimicrobial activity. Enhanced Na+-driven MΦ-function requires the osmoprotective transcription factor nuclear factor of activated T cells 5 (NFAT5), which augments NO production and contributes to increased autophagy. However, the mechanism of Na+-sensing in MΦ remained unclear. High extracellular Na+ levels (HS) trigger a substantial Na+-influx and Ca2+ loss. Here, we show that the Na+/ Ca2+-exchanger 1 (NCX1/ solute carrier family 8 member A1 (SLC8A1)) plays a critical role in HS-triggered Na+-influx, concomitant Ca2+ efflux and subsequent NFAT5 accumulation. Moreover, interfering with NCX1-activity impairs HS-boosted inflammatory signaling, infection-triggered autolysosome formation and subsequent antibacterial activity. Taken together, this demonstrates that NCX1 is able to sense Na+ and is required for amplifying inflammatory and antimicrobial MΦ responses upon HS exposure. Manipulating NCX1 offers a new strategy to regulate MΦ function.
2020-06-29 | GSE136662 | GEO
Project description:The skin protects the human body against dehydration and harmful challenges. Keratinocytes (KCs) are the most frequent epidermal cells, and it is anticipated that KC-mediated transport of Na+ ions creates a physiological barrier of high osmolality against the external environment. We studied in KCs the role of NFAT5, a transcription factor whose activity is controlled by osmotic stress. Cultured KCs from adult mice secrete more than 300 proteins, and upon NFAT5 ablation, the secretion of several matrix proteinases, including metalloproteinase-3 (Mmp3) and kallikrein-related peptidase 7 (Klk7), was markedly enhanced. An increase in Mmp3 and Klk7 RNA levels was also detected in transcriptomes of Nfat5-/- KCs, along with increases of numerous components of ‘Epidermal Differentiation Complex’ (EDC), as proline-rich Sprr and S100 proteins. NFAT5 and Mmp3 are co-expressed in basal KCs from fetal and adult skin but not in skin of newborn mice. This is correlated with a strong increase in Mmp3 and Klk7 expression in KCs of newborn mice and suggests, along with the fragile epidermis of adult Nfat5-/- mice, a suppressive effect of NFAT5 on the expression of matrix proteases in skin. Our data suggest that NFAT5 controls the expression of matrix proteases in skin and contributes to the many fold changes during embryonal skin development and skin integrity in adults.
2021-11-16 | PXD028675 | Pride
Project description:The skin protects the human body against dehydration and harmful challenges. Keratinocytes (KCs) are the most frequent epidermal cells, and it is anticipated that KC-mediated transport of Na+ ions creates a physiological barrier of high osmolality against the external environment. We studied in KCs the role of NFAT5, a transcription factor whose activity is controlled by osmotic stress. Cultured KCs from adult mice secrete more than 300 proteins, and upon NFAT5 ablation, the secretion of several matrix proteinases, including metalloproteinase-3 (Mmp3) and kallikrein-related peptidase 7 (Klk7), was markedly enhanced. An increase in Mmp3 and Klk7 RNA levels was also detected in transcriptomes of Nfat5-/- KCs, along with increases of numerous components of ‘Epidermal Differentiation Complex’ (EDC), as proline-rich Sprr and S100 proteins. NFAT5 and Mmp3 are co-expressed in basal KCs from fetal and adult skin but not in skin of newborn mice. This is correlated with a strong increase in Mmp3 and Klk7 expression in KCs of newborn mice and suggests, along with the fragile epidermis of adult Nfat5-/- mice, a suppressive effect of NFAT5 on the expression of matrix proteases in skin. Our data suggest that NFAT5 controls the expression of matrix proteases in skin and contributes to the many fold changes during embryonal skin development and skin integrity in adults.
2021-12-29 | GSE184179 | GEO
Project description:The skin protects the human body against dehydration and harmful challenges. Keratinocytes (KCs) are the most frequent epidermal cells, and it is anticipated that KC-mediated transport of Na+ ions creates a physiological barrier of high osmolality against the external environment. We studied in KCs the role of NFAT5, a transcription factor whose activity is controlled by osmotic stress. Cultured KCs from adult mice secrete more than 300 proteins, and upon NFAT5 ablation, the secretion of several matrix proteinases, including metalloproteinase-3 (Mmp3) and kallikrein-related peptidase 7 (Klk7), was markedly enhanced. An increase in Mmp3 and Klk7 RNA levels was also detected in transcriptomes of Nfat5-/- KCs, along with increases of numerous components of ‘Epidermal Differentiation Complex’ (EDC), as proline-rich Sprr and S100 proteins. NFAT5 and Mmp3 are co-expressed in basal KCs from fetal and adult skin but not in skin of newborn mice. This is correlated with a strong increase in Mmp3 and Klk7 expression in KCs of newborn mice and suggests, along with the fragile epidermis of adult Nfat5-/- mice, a suppressive effect of NFAT5 on the expression of matrix proteases in skin. Our data suggest that NFAT5 controls the expression of matrix proteases in skin and contributes to the many fold changes during embryonal skin development and skin integrity in adults.
2021-12-29 | GSE184178 | GEO
Project description:Comaprison of the gene expression profiles of the spleen between wild type and Brx haploinsuffieint mice Nuclear factor of activated T-cells 5 (NFAT5) is a transcription factor that regulates hyperosmolarity-responsive genes and helps activated T lymphocytes adapt to and discharge their functions in hyperosmolar environments. We report here that the Rho-type guanine nucleotide exchange factor (GEF) Brx is essential for increased NFAT5 expression in response to osmotic stress in lymphoid tissues. Indeed, brx haploinsufficient mice expressed significantly less NFAT5 in their spleens than wild type controls and their splenocytes had a defective response to osmotic stress in vitro. Haploinsufficient mice also had smaller-sized spleens containing fewer splenocytes, as well as a defective immunoglobulin response to ovalbumin compared to wild type mice. The Brx GEF domain and the p38 mitogen-activated kinase (MAPK) cascade were both required for osmotic stress-mediated induction of NFAT5 in Jurkat cells. Brx physically interacted with the cJun kinase (JNK)-interacting protein (JIP) 4, a scaffold protein for activation of the p38 MAPK cascade that was required for osmotic stress-induced NFAT5 expression. Thus, Brx is a signal integrator for the adaptive response to osmotic stress in the immune system, activating small G proteins, attracting JIP4 and stimulating p38 MAPK, ultimately increasing the expression of NFAT5 and activating hyperosmolarity protective genes, a phenomenon crucial for proper immune function in hyperosmolar environments, such as inflammatory sites and immune organs. Keywords: Genetic modification Two-condition experiment: Wild type and Brx haploinsuffient, 3 replicates, labeling swap for each
2009-02-09 | E-GEOD-10117 | biostudies-arrayexpress
Project description:We compared tissue Na+ storage in salt sensitive spontaneously hypertensive rats (SHR) versus salt resistant normotensive Brown Norway (BN) rats after salt loading (10 days drinking 1% NaCl solution), the SHR showed significant parallel increase in osmotically inactive Na+ storage in the skin while no significant changes in skin electrolyte concentrations were observed in BN rats. SHR rats after salt treatment exhibited a nonsignificant decrease in skin blood capillary number (rarefaction) while BN rats showed significantly increased skin blood capillary density. Analysis of dermal gene expression profiles in BN rats after salt treatment showed significant up-regulation of genes involved in angiogenesis and proliferation of endothelial cells contrary to the SHR.
2023-01-01 | E-MTAB-11355 | biostudies-arrayexpress
Project description:Comaprison of the gene expression profiles of the spleen between wild type and Brx haploinsuffieint mice Nuclear factor of activated T-cells 5 (NFAT5) is a transcription factor that regulates hyperosmolarity-responsive genes and helps activated T lymphocytes adapt to and discharge their functions in hyperosmolar environments. We report here that the Rho-type guanine nucleotide exchange factor (GEF) Brx is essential for increased NFAT5 expression in response to osmotic stress in lymphoid tissues. Indeed, brx haploinsufficient mice expressed significantly less NFAT5 in their spleens than wild type controls and their splenocytes had a defective response to osmotic stress in vitro. Haploinsufficient mice also had smaller-sized spleens containing fewer splenocytes, as well as a defective immunoglobulin response to ovalbumin compared to wild type mice. The Brx GEF domain and the p38 mitogen-activated kinase (MAPK) cascade were both required for osmotic stress-mediated induction of NFAT5 in Jurkat cells. Brx physically interacted with the cJun kinase (JNK)-interacting protein (JIP) 4, a scaffold protein for activation of the p38 MAPK cascade that was required for osmotic stress-induced NFAT5 expression. Thus, Brx is a signal integrator for the adaptive response to osmotic stress in the immune system, activating small G proteins, attracting JIP4 and stimulating p38 MAPK, ultimately increasing the expression of NFAT5 and activating hyperosmolarity protective genes, a phenomenon crucial for proper immune function in hyperosmolar environments, such as inflammatory sites and immune organs. Keywords: Genetic modification
2009-02-09 | GSE10117 | GEO
Project description:Purpose: Investigate effects of high salt on human macrophage activation Methods: Human monocytes-derived macrophages were treated by additional 51mM NaCl for 24 hours (NaCl groups) or not (Control groups). mRNA profiles were generated by RNA-Seq, in triplicate, using Ion proton（Life tech). qRT–PCR validation was performed using SYBR Green assays. Results: High salt significantly promotes pro-inflammatory gene expressions,while suppresses the expressions of anti-inflammatory genes and pro-endocytic genes in human macrophages. Conclusions: Our results identify a novel macrophage activation state, M(Na), and high salt as a potential environmental risk factor for lung inflammation through the induction of M(Na)
2015-09-23 | GSE68482 | GEO
Project description:Fibroblast growth factor-23 (FGF23) is a bone-derived hormone that has recently received much attention due to its association with the progression of chronic kidney disease, cardiovascular disease, and associated mortality. Extracellular sodium ion concentration ([Na+]) plays a significant role in bone metabolism. Both hyponatremia (low serum [Na+]) and hypernatremia (high serum [Na+]) have been shown to affect bone remodeling. However, nothing is known about the impact of [Na+] on FGF23 production. Here, we show that elevated [Na+] (by +20 mM) suppressed FGF23 formation, whereas low [Na+] (by -20 mM) led to an increase in FGF23 synthesis in the osteoblast-like cell line UMR-106. Similar bidirectional changes in FGF23 were observed when osmolality was altered by mannitol but not by urea, suggesting a role of tonicity in FGF23 formation. Moreover, these changes in FGF23 were inversely proportional to the expression of NFAT5 (nuclear factor of activated T cells-5), a transcription factor responsible for tonicity-mediated cellular adaptations. On the other hand, arginine vasopressin (AVP), which is often responsible for hyponatremia, did not affect FGF23 production. Next, comprehensive and unbiased RNA-seq analysis of UMR-106 cells exposed to low vs. high [Na+] revealed several novel genes involved in cellular adaptation to altered tonicity. Additional analysis of cells with Crisp-Cas9 mediated NFAT5 deletion indicated that NFAT5 controls numerous genes associated with FGF23 synthesis, thereby confirming its role in [Na+]-mediated FGF23 regulation. In line with these findings, in a pilot study, we found that human hyponatremic patients have higher FGF23 levels. Our results suggest that [Na+] is a critical regulator of FGF23 synthesis.
2023-06-23 | GSE235694 | GEO
Project description:The aim of this study was to characterize the tissue tolerance mechanisms of rice under salt stress. Our preliminary experiment identified a japonica rice landrace Shuzenji-kokumai (SZK), which is considered to be tissue-tolerant because it can maintain better growth than salt-sensitive rice while having a high Na+ concentration in the shoots under salt stress. These mechanisms differ from those of most salt-tolerant rice varieties, which have low Na+ concentrations in the shoots. We compared the physiological and molecular characteristics of SZK with those of FL478, a salt-tolerant variety, and Kunishi, a salt-sensitive variety. Under salt stress conditions, SZK accumulated high levels of Na+ in roots, leaf sheaths, and leaf blades, which were almost as high as those in the salt-sensitive Kunishi. Simultaneously, SZK maintained better growth and physiological status, as determined by its higher dry weight, lower electrolyte leakage ratio, and lower malondialdehyde concentration. OsNHX1 and OsNHX2 were up-regulated in the leaf sheaths of SZK, suggesting that Na+ is compartmentalized in the vacuole to avoid Na+ toxicity. In contrast, FL478 showed up-regulation of OsHKT1;5 and OsSOS1 in the roots, which exclude Na+ from the shoots. RNA-seq analysis showed that 4623 and 1998 differentially expressed genes (DEGs) were detected in the leaf sheaths and leaf blades of SZK, respectively. Among them, the HSP (heat shock protein) gene expression was highly up-regulated only in SZK, indicating that SZK protects against the protein damage caused by Na+ toxicity. Our findings suggest that SZK has atypical survival mechanisms under salt-stress conditions. These mechanisms offer potential traits for improving salt tolerance in rice.
2024-05-08 | GSE266657 | GEO