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Corticosterone is produced by mTrECs. (A) Corticosterone levels were determined in control medium (Ctr) or ECCM. (B) Correlation of the induction of Ms4a8a or Ym1 with corticosterone concentrations analyzed in different preparations of ECCM. (C) Genes significantly regulated in microarray analysis linked to Gene Ontology term "response to glucocorticoids" (GO::0051384). (D) BMDCs were incubated for 16 h with ECCM. After RNA extraction, expression of Tsc22d3 or Dusp1 was analyzed by qPCR. Data are shown as relative expression (rE) to Actb. *p , 0.05.
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Airway epithelial cells mount a tolerogenic microenvironment that reduces the proinflammatory potential of respiratory dendritic cells (DCs). We recently demonstrated that tracheal epithelial cells continuously secrete soluble mediators that affect the reactivity of local innate immune cells. Using transcriptional profiling, we now observed that co...
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... probe sets that had a p value #0.05 and a fold change $2 or #0.5 were further investigated. that in medium that was incubated for 48 h in the presence of mTrECs, 40-50 pg/ml corticosterone was detectable (Fig. 4A). In contrast, no relevant corticosterone levels were detectable in control medium, which excludes a contamination with bioactive glucocorticoids and argues for an active generation by tracheal epithelial cells. Because corticosterone levels and the potential of ECCM to induce Ms4a8a and Ym1 expression varied from the different mTrEC ...
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... tracheal epithelial cells. Because corticosterone levels and the potential of ECCM to induce Ms4a8a and Ym1 expression varied from the different mTrEC preparations, we tested if these two variables correlated with one another. Indeed, we observed significant cor- relation of corticosterone concentrations in ECCM with the fold increase of Ms4a8a (Fig. 4B). However, Ym1 induction did not show significant correlation with corticosterone levels. Additionally, we observed by pathway analysis of the microarray data that genes related to the response to glucocorticoids were significantly over- represented (p = 3.4 3 10 24 , Gene Ontology number GO::0051384) (Fig. 4C). Furthermore, we analyzed ...
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... with the fold increase of Ms4a8a (Fig. 4B). However, Ym1 induction did not show significant correlation with corticosterone levels. Additionally, we observed by pathway analysis of the microarray data that genes related to the response to glucocorticoids were significantly over- represented (p = 3.4 3 10 24 , Gene Ontology number GO::0051384) (Fig. 4C). Furthermore, we analyzed the expression of two well- described GR target genes, Tsc22d3 and Dusp1, which are related to inflammatory processes (19). Both genes were significantly in- duced by ECCM, thus further supporting a role of glucocorticoids in ECCM-mediated gene expression in pulmonary DCs (Fig. ...
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... 24 , Gene Ontology number GO::0051384) (Fig. 4C). Furthermore, we analyzed the expression of two well- described GR target genes, Tsc22d3 and Dusp1, which are related to inflammatory processes (19). Both genes were significantly in- duced by ECCM, thus further supporting a role of glucocorticoids in ECCM-mediated gene expression in pulmonary DCs (Fig. ...
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Citations
... Различная экспрессия изоформ 11β-ОН ДГ в тканях определяет тканеспецифичность эффектов ГК [37]. Так, эпителиальные клетки респираторного тракта способны снижать провоспалительный потенциал дендритных клеток, в которых обнаружены ГР, путем реактивации неактивного дегидрокортикостерона [48]. Выявлен ряд генетических полиморфизмов 11β-ОН ДГ 1-го и 2-го типа, влияющих на функциональную активность этого фермента и, как следствие, определяющих развитие некоторых заболеваний, в патогенезе которых важную роль играет кортизол [49]. ...
В настоящее время возрастает актуальность изучения тонких молекулярных механизмов реализации иммуномодулирующих эффектов глюкокортикоидов с целью прогнозирования индивидуальных особенностей реагирования на различные внешние воздействия, в том числе инфекции, хронический стресс, а также развития аутоиммунных заболеваний. В обзоре обсуждаются иммунотропные эффекты глюкокортикоидов с учетом факторов регуляции их секреции и механизмы реализации этих эффектов. Особое внимание уделяется роли глюкокортикоидных рецепторов, а также систем транспорта и деградации кортизола. Представлены современные научные данные о структуре, вариабельности и особенностях функционирования глюкокортикоидного рецептора, роли полиморфизма гена глюкокортикоидного рецептора, систем посттрансляционной модификации в многообразии эффектов кортизола. Появление новых данных, касающихся иммунотропных эффектов глюкокортикоидных гормонов, обосновывает проведение дальнейших исследований, направленных на выявление экспрессии полиморфных генов с целью более глубокой персонализации профилактических и лечебных мероприятий.
Currently, the topicality of studying of the fine molecular mechanisms of glucocorticoids immunomodulatory effects is increasing in order to predict the individual features of the response to various external influences, including infections, chronic stress, and the development of autoimmune diseases. The review discusses the immunotropic effects of glucocorticoids, taking into account the factors regulating their secretion, and the mechanisms of these effects. Particular attention is paid to the glucocorticoid receptors role, as well as the systems of cortisol transport and degradation. Modern scientific data on the structure, variability and features of the glucocorticoid receptor functioning are presented, as well as on the role of glucocorticoid receptor gene polymorphism and post- translational modification systems in the variety of cortisol effects. The emergence of new data regarding the immunotropic effects of glucocorticoid hormones justifies further research aimed at identifying the expression of polymorphic genes in order to deeper personalization of preventive and therapeutic measures.
... Interestingly, TREM-1 protein expression in macrophages is associated with amplification of the inflammatory immune response and secretion of proinflammatory cytokines, such as IL-6 [53]. Additionally, while Arg2 seems to have a dual role in both M1 and M2 macrophages, expression of Ms4a8a is related to the induction of M2 macrophages [54]. Furthermore, we found Ly6c2 and Ccr2, both of which are associated with M1 (inflammatory) macrophages, to be highly expressed in infiltrating macrophages (Fig. 4a, blue asterisk). ...
... We also showed, for the first time, that another member of the MS4A family, Ms4a8a, was predominantly expressed in macrophages that infiltrate the CNS but not in microglia (Fig. 5b). Interestingly, MS4A8A was identified as a protein expressed by tumor-associated macrophages and its expression seemed to be a marker for M2 macrophages [54,78]. Although further studies will be needed to understand the exact function of these proteins, the results presented here suggest that specific MS4A proteins might play distinct roles in infiltrating macrophages and microglia during neuroinflammation. ...
Background:
In the healthy central nervous system (CNS), microglia are found in a homeostatic state and peripheral macrophages are absent from the brain. Microglia play key roles in maintaining CNS homeostasis and acting as first responders to infection and inflammation, and peripheral macrophages infiltrate the CNS during neuroinflammation. Due to their distinct origins and functions, discrimination between these cell populations is essential to the comprehension of neuroinflammatory disorders. Studies comparing the gene profiles of microglia and peripheral macrophages, or macrophages in vitro-derived from bone marrow, under non-infectious conditions of the CNS, have revealed valuable microglial-specific genes. However, studies comparing gene profiles between CNS-infiltrating macrophages and microglia, when both are isolated from the CNS during viral-induced neuroinflammation, are lacking.
Methods:
We isolated, via flow cytometry, microglia and infiltrating macrophages from the brains of Theiler's murine encephalomyelitis virus-infected C57BL/6 J mice and used RNA-Seq, followed by validation with qPCR, to examine the differential transcriptional profiles of these cells. We utilized primary literature defining subcellular localization to determine whether or not particular proteins extracted from the transcriptional profiles were expressed at the cell surface. The surface expression and cellular specificity of triggering receptor expressed on myeloid cells 1 (TREM-1) protein were examined via flow cytometry. We also examined the immune response gene profile within the transcriptional profiles of these isolated microglia and infiltrating macrophages.
Results:
We have identified and validated new microglial- and macrophage-specific genes, encoding cell surface proteins, expressed at the peak of neuroinflammation. TREM-1 protein was confirmed to be expressed by infiltrating macrophages, not microglia, at the peak of neuroinflammation. We also identified both unique and redundant immune functions, through examination of the immune response gene profiles, of microglia and infiltrating macrophages during neurotropic viral infection.
Conclusions:
The differential expression of cell surface-specific genes during neuroinflammation can potentially be used to discriminate between microglia and macrophages as well as provide a resource that can be further utilized to target and manipulate specific cell responses during neuroinflammation.
... The immature status of DC has been previously suggested to account for the immune dysregulation in C. neoformans-infected mice following TNF-␣ depletion (18). However, more recent studies with other antigens and/or pathogens suggest that DC can become either classically or alternatively activated, which then directs the subsequent type of T cell polarization (21,22). Classically activated DC (DC1) show robust production of Th1/Th17-polarizing cytokines along with high surface expression of major histocompatibility complex class II (MHC-II) and costimulatory molecules (23). ...
... Expression of Malat1 in AECs-DCs co-culture system. The tracheal epithelial cells have been found to regulate the gene expression in BMDCs (39), but whether these respiratory epithelial cell could modulate the long-non coding RNA expression is unclear. To contact the DCs with alveolar epithelial cells (MLE-12), MLE-12 cells were cultured on top of inverted filter inserts. ...
... Given their frequent contact with inhaled antigens or microbial substances, immunomodulatory functions appear particularly important in the trachea (40). Previous study (39) have revealed the interrelationship between epithelial cells and DCs at the transcriptional level. In this study, we provide the first evidence that Malat1 can modulate the maturation process, pro-inflammatory cytokine secretion and apoptosis in AECs-conditioned DCs as Schematic representation in Fig. 6. ...
Airway epithelial cells (AECs) are the first point of contact with airborne antigens and are able to instruct resident immune cells to appropriate immune responses. Previous studies have shown that the abnormal expression of metastasis-associated lung adenocarcinoma transcript 1 (Malat1) was associated with tumorigenesis, progression, metastasis, and apoptosis in many cancer types. However, little is known about its functional involvement in the cross-talk of AECs with dendritic cells (DCs). The aim of the present study was to identify Malat1 as a novel epithelial cell-derived immune-modulating factor that contributes to the specific inflammatory-immune airway microenvironment. By using an in vitro co-culture model, where layers of AECs can interact with DCs, and transfecting Malat1 siRNA in AECs, AEC-conditioned DCs were harvested for further analysis of the celluar phenotype, secretion of inflammatory chemokines, and expression of apoptotic markers. The present study clearly demonstrated that Malat1 modulates the maturation process, pro-inflammatory cytokine secretion and apoptosis in AECs-conditioned DCs.
... In addition, Lebson et al. reported GILZ induction in BMDCs exposed to A20-and B16-tumor cells conditioned medium, pointing to a role for soluble factors in this increased expression (26). These factors may include known GILZ inducers as reported in epithelial cellconditioned medium-treated BMDCs (67). Additional studies have pointed to GILZ levels modulation in cells other than DCs during chronic inflammation. ...
... The contribution of GILZ induction to GCs therapeutic effects is supported by several studies, two of them having assessed it in DCs. First, restoration of GILZ (26,45,67), immunosuppressive drugs as synthetic GCs, rapamycin, and mitomycine C (11), fungal proteases (68), and cancer microenvironment (26). So far, the only exogenous GILZ repressor reported in DCs is LPS (26,27). ...
Dendritic cells (DCs) are key antigen-presenting cells that control the induction of both tolerance and immunity. Understanding the molecular mechanisms regulating DCs commitment toward a regulatory- or effector-inducing profile is critical for better designing prophylactic and therapeutic approaches. Initially identified in dexamethasone-treated thymocytes, the glucocorticoid-induced leucine zipper (GILZ) protein has emerged as a critical factor mediating most, but not all, glucocorticoids effects in both non-immune and immune cells. This intracellular protein exerts pleiotropic effects through interactions with transcription factors and signaling proteins, thus modulating signal transduction and gene expression. GILZ has been reported to control the proliferation, survival, and differentiation of lymphocytes, while its expression confers anti-inflammatory phenotype to monocytes and macrophages. In the past twelve years, a growing set of data has also established that GILZ expression in DCs is a molecular switch controlling their T-cell-priming capacity. Here, after a brief presentation of GILZ isoforms and functions, we summarize current knowledge regarding GILZ expression and regulation in DCs, in both health and disease. We further present the functional consequences of GILZ expression on DCs capacity to prime effector or regulatory T-cell responses and highlight recent findings pointing to a broader role of GILZ in the fine tuning of antigen capture, processing, and presentation by DCs. Finally, we discuss future prospects regarding the possible roles for GILZ in the control of DCs function in the steady state and in the context of infections and chronic pathologies.
... Expression of Malat1 in AECs-DCs co-culture system. The tracheal epithelial cells have been found to regulate the gene expression in BMDCs (39), but whether these respiratory epithelial cell could modulate the long-non coding RNA expression is unclear. To contact the DCs with alveolar epithelial cells (MLE-12), MLE-12 cells were cultured on top of inverted filter inserts. ...
... Given their frequent contact with inhaled antigens or microbial substances, immunomodulatory functions appear particularly important in the trachea (40). Previous study (39) have revealed the interrelationship between epithelial cells and DCs at the transcriptional level. In this study, we provide the first evidence that Malat1 can modulate the maturation process, pro-inflammatory cytokine secretion and apoptosis in AECs-conditioned DCs as Schematic representation in Fig. 6. ...
Oxidized low-density lipoprotein (oxLDL)-induced injury and apoptosis of endothelial cells are important initial events in numerous cardiovascular diseases. Following activation by oxLDL, monocytes adhere to endothelial cells, migrate into the subendothelial spaces and then undergo differentiation into macrophages, which subsequently induces the formation of atherosclerotic lesions. However, the mechanisms underlying the activation of macrophage differentiation by oxLDL-treated endothelial cells remain unclear. In the present study, it was demonstrated that exosomal metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was increased in oxLDL-treated human umbilical vein endothelial cells. When co-cultured with monocytes, exosomes extracted from oxLDL-treated HUVECs were endocytosed. Furthermore, exosomes derived from oxLDL-treated endothelial cells were revealed to promote M2 macrophage polarization, as reverse transcription-quantitative polymerase chain reaction, western blotting and ELISA analyses demonstrated increases in the expression of M2 macrophage markers, including macrophage mannose receptor 1 (also termed CD206), arginase-1 and interleukin (IL)-10, and decreases in the expression of the M1 macrophage marker, IL-12. Furthermore, the suppression of MALAT1 expression in monocytes was demonstrated to reverse exosome-mediated M2 macrophage polarization. In conclusion, the results of the present study revealed a novel mechanism underlying the onset of atherogenesis associated with endothelial cells and macrophages: Exosomal MALAT1 derived from oxLDL-treated endothelial cells promoted M2 macrophage polarization. This result may provide a novel scientific basis for the understanding of atherosclerosis progression.
... By contrast, aaAPCs were described to cause amelioration of disease by promoting tissue repair, tissue regeneration and oligodendrocyte differentiation (reviewed in (Jiang et al. 2014)). Interestingly, DCs have been described to express markers of aaAPC (Weitnauer et al. 2014). All these APC populations may both promote and suppress disease outcome by influencing T-cell responses in CNS autoimmunity. ...
The importance of CD11c+ antigen-presenting cells (APCs) in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) is well accepted and the gate keeper function of perivascular CD11c+ APCs has been demonstrated. CD11c can be expressed by APCs from external sources or by central nervous system (CNS) resident APCs such as microglia. Yet, changes in the gene expression pattern of CNS CD11c+ APCs during disease are still unclear and differentially expressed genes might play a decisive role in EAE progression. Due to their low numbers in the diseased brain and due to the absence of considerable numbers in the healthy CNS, analysis of CNS CD11c+ cells is technically difficult. To ask whether the CD11c+ APC population contributes to remission of EAE disease, we used Illumina deep mRNA sequencing (RNA-Seq) and quantitative real time polymerase chain reaction (qRT-PCR) analyses to identify the transcriptome of CD11c+ APCs during disease course. We identified a battery of genes that were significantly regulated during the exacerbation of the disease compared to remission and relapse. Three of these genes, Arginase-1, Chi3l3 and Ms4a8a, showed a higher expression at the exacerbation than at later time points during the disease, both in SJL/J and in C57BL/6 mice, and could be attributed to alternatively activated APCs. Expression of Arginase-1, Chi3l3 and Ms4a8a genes was linked to the disease phase of EAE rather than to disease score. Expression of these genes suggested that APCs resembling alternatively activated macrophages are involved during the first wave of neuroinflammation and can be directly associated with the disease progress.
... The immature status of DC has been previously suggested to account for the immune dysregulation in C. neoformans-infected mice following TNF-␣ depletion (18). However, more recent studies with other antigens and/or pathogens suggest that DC can become either classically or alternatively activated, which then directs the subsequent type of T cell polarization (21,22). Classically activated DC (DC1) show robust production of Th1/Th17-polarizing cytokines along with high surface expression of major histocompatibility complex class II (MHC-II) and costimulatory molecules (23). ...
Unlabelled:
Anti-tumor necrosis factor alpha (anti-TNF-α) therapies have been increasingly used to treat inflammatory diseases and are associated with increased risk of invasive fungal infections, including Cryptococcus neoformans infection. Using a mouse model of cryptococcal infection, we investigated the mechanism by which disruption of early TNF-α signaling results in the development of nonprotective immunity against C. neoformans We found that transient depletion of TNF-α inhibited pulmonary fungal clearance and enhanced extrapulmonary dissemination of C. neoformans during the adaptive phase of the immune response. Higher fungal burdens in TNF-α-depleted mice were accompanied by markedly impaired Th1 and Th17 responses in the infected lungs. Furthermore, early TNF-α depletion also resulted in disrupted transcriptional initiation of the Th17 polarization program and subsequent upregulation of Th1 genes in CD4(+) T cells in the lung-associated lymph nodes (LALN) of C. neoformans-infected mice. These defects in LALN T cell responses were preceded by a dramatic shift from a classical toward an alternative activation of dendritic cells (DC) in the LALN of TNF-α-depleted mice. Taken together, our results indicate that early TNF-α signaling is required for optimal DC activation, and the initial Th17 response followed by Th1 transcriptional prepolarization of T cells in the LALN, which further drives the development of protective immunity against cryptococcal infection in the lungs. Thus, administration of anti-TNF-α may introduce a particularly greater risk for newly acquired fungal infections that require generation of protective Th1/Th17 responses for their containment and clearance.
Importance:
Increased susceptibility to invasive fungal infections in patients on anti-TNF-α therapies underlines the need for understanding the cellular effects of TNF-α signaling in promoting protective immunity to fungal pathogens. Here, we demonstrate that early TNF-α signaling is required for classical activation and accumulation of DC in LALN of C. neoformans-infected mice. Subsequent transcriptional initiation of Th17 followed by Th1 programming in LALN results in pulmonary accumulation of gamma interferon- and interleukin-17A-producing T cells and effective fungal clearance. All of these crucial steps are severely impaired in mice that undergo anti-TNF-α treatment, consistent with their inability to clear C. neoformans This study identified critical interactions between cells of the innate immune system (DC), the emerging T cell responses, and cytokine networks with a central role for TNF-α which orchestrate the development of the immune protection against cryptococcal infection. This information will be important in aiding development and understanding the potential side effects of immunotherapies.
... 147 However, expression and GC synthesis by 11b-HSD1 has recently been reported to take place in adult murine lungs 148,149 and isolated murine airway epithelial cells. 150 Interestingly, pulmonary GC synthesis was elevated under inflammatory conditions, indicating a negative feedback mechanism. 149 Moreover, it was demonstrated that epithelial-derived GC, together with PGE 2 , are able to induce tolerogenic dendritic cells. ...
... 149 Moreover, it was demonstrated that epithelial-derived GC, together with PGE 2 , are able to induce tolerogenic dendritic cells. 119,150 ...
The lung is ventilated by thousand liters of air per day. Inevitably, the respiratory system comes into contact with airborne microbial compounds, most of them harmless contaminants. Airway epithelial cells are known to have innate sensor functions, thus being able to detect microbial danger. To avoid chronic inflammation, the pulmonary system has developed specific means to control local immune responses. Even though airway epithelial cells can act as proinflammatory promoters, we propose that under homeostatic conditions airway epithelial cells are important modulators of immune responses in the lung. In this review, we discuss epithelial cell regulatory functions that control reactivity of professional immune cells within the microenvironment of the airways and how these mechanisms are altered in pulmonary diseases. Regulation by epithelial cells can be divided into two mechanisms: (1) mediators regulate epithelial cells' innate sensitivity in cis and (2) factors are produced that limit reactivity of immune cells in trans.Mucosal Immunology advance online publication, 2 December 2015; doi:10.1038/mi.2015.126.
... AECs also modulate the reactivity of local immune cells. T-cell activation and innate immune reactions are controlled through the secretion of immune-modulatory factors including TSLP, IL-10, nitric oxide, LL37, TGF-, prostaglandin E 2 and glucocorticoids (Bingisser and Holt, 2001; Kandler et al., 2006; Schmidt et al., 2011; Weitnauer et al., 2014 ). Moreover, local immune cells are found in close proximity to airway epithelial cells (Jahnsen et al., 1998), suggesting cell–cell interactions might also contribute to modulatory functions . ...
... We have previously shown that airway epithelial cells are able to modulate activation of innate immune cells and T-cells by secreting a variety of soluble, immune-modulatory substances (Mayer et al., 2008; Schmidt et al., 2011; Weitnauer et al., 2014). As airway epithelial cells come into close contact with innate immune cells, we now wanted to assess whether direct cell–cell contacts are also involved in epithelial cell-mediated immune-modulation. ...
