Calcineurin-nuclear factor of activated T cells (CN-NFAT) inhibitors are widely clinically used drugs for immunosuppression, but besides their required T cell response inhibition, they also undesirably affect innate immune cells. Disruption of innate immune cell function can explain the observed susceptibility of CN-NFAT inhibitor-treated patients to opportunistic fungal infections. Neutrophils play an essential role in innate immunity as a defense against pathogens; however, the effect of CN-NFAT inhibitors on neutrophil function was poorly described. Thus, we tested the response of human neutrophils to opportunistic fungal pathogens, namely Candida albicans and Aspergillus fumigatus, in the presence of CN-NFAT inhibitors. Here, we report that the NFAT pathway members were expressed in neutrophils and mediated part of the neutrophil response to pathogens. Upon pathogen exposure, neutrophils underwent profound transcriptomic changes with subsequent production of effector molecules. Importantly, genes and proteins involved in the regulation of the immune response and chemotaxis, including the chemokines CCL2, CCL3, and CCL4 were significantly upregulated. The presence of CN-NFAT inhibitors attenuated the expression of these chemokines and impaired the ability of neutrophils to chemoattract other immune cells. Our results amend knowledge about the impact of CN-NFAT inhibition in human neutrophils.

• MeSH
• Aspergillus fumigatus imunologie   MeSH
• Candida albicans imunologie   MeSH
• chemotaxe MeSH
• kalcineurin * metabolismus   MeSH
• lidé MeSH
• mykózy imunologie   MeSH
• neutrofily * imunologie   metabolismus   MeSH
• signální transdukce * MeSH
• transkripční faktory NFATC * metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Prostate cancer develops through malignant transformation of the prostate epithelium in a stepwise, mutation-driven process. Although activator protein-1 transcription factors such as JUN have been implicated as potential oncogenic drivers, the molecular programs contributing to prostate cancer progression are not fully understood. METHODS: We analyzed JUN expression in clinical prostate cancer samples across different stages and investigated its functional role in a Pten-deficient mouse model. We performed histopathological examinations, transcriptomic analyses and explored the senescence-associated secretory phenotype in the tumor microenvironment. RESULTS: Elevated JUN levels characterized early-stage prostate cancer and predicted improved survival in human and murine samples. Immune-phenotyping of Pten-deficient prostates revealed high accumulation of tumor-infiltrating leukocytes, particularly innate immune cells, neutrophils and macrophages as well as high levels of STAT3 activation and IL-1β production. Jun depletion in a Pten-deficient background prevented immune cell attraction which was accompanied by significant reduction of active STAT3 and IL-1β and accelerated prostate tumor growth. Comparative transcriptome profiling of prostate epithelial cells revealed a senescence-associated gene signature, upregulation of pro-inflammatory processes involved in immune cell attraction and of chemokines such as IL-1β, TNF-α, CCL3 and CCL8 in Pten-deficient prostates. Strikingly, JUN depletion reversed both the senescence-associated secretory phenotype and senescence-associated immune cell infiltration but had no impact on cell cycle arrest. As a result, JUN depletion in Pten-deficient prostates interfered with the senescence-associated immune clearance and accelerated tumor growth. CONCLUSIONS: Our results suggest that JUN acts as tumor-suppressor and decelerates the progression of prostate cancer by transcriptional regulation of senescence- and inflammation-associated genes. This study opens avenues for novel treatment strategies that could impede disease progression and improve patient outcomes.

• MeSH
• fosfohydroláza PTEN * genetika   metabolismus   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádorové mikroprostředí * imunologie   MeSH
• nádory prostaty * patologie   genetika   metabolismus   MeSH
• progrese nemoci * MeSH
• protoonkogenní proteiny c-jun metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• sekreční fenotyp asociovaný se senescencí MeSH
• stanovení celkové genové exprese MeSH
• stárnutí buněk genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: The immune systems of both the mother and the newborn face significant challenges during birth. Proper immune regulation after birth is essential for the survival of neonates. Numerous studies have demonstrated that the neonatal immune system is relatively immature, particularly in its adaptive arm, placing the primary responsibility for immune surveillance on innate immunity. METHODS: Given the significant role of neutrophils in protecting the neonate after birth, we conducted a study investigating the properties of neutrophils in newborn cord blood using various methodological approaches. RESULTS: Our findings demonstrate the presence of immature low-density neutrophils in the cord blood, which are likely responsible for the observed elevated expression of genes coding for proteins essential to antimicrobial response, including myeloperoxidase, neutrophils elastase, and defensins. DISCUSSION: We propose that these cells function normally and support the protection of newborns early after birth. Furthermore, our results suggest that the mode of delivery might significantly influence the programming of neutrophil function. The presented findings emphasize the importance of distinct neutrophil subpopulations in neonatal immunity and their potential impact on early postnatal health.

• MeSH
• antiinfekční látky * metabolismus   MeSH
• fetální krev MeSH
• lidé MeSH
• neutrofily * MeSH
• novorozenec MeSH
• přirozená imunita MeSH
• proteiny metabolismus   MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• časopisecké články MeSH
• komentáře MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Integrated behavioral paradigms such as nociceptive processing coupled to anti-nociceptive responsiveness include systemically-mediated states of alertness, vigilance, motivation, and avoidance. Within a historical and cultural context, opium and its biologically active compounds, codeine and morphine, have been widely used as frontline anti-nociceptive agents. In eukaryotic cells, opiate alkaloids and opioid peptides were evolutionarily fashioned as regulatory factors in neuroimmune, vascular immune, and systemic immune communication and auto-immunoregulation. The significance of opioidergic regulation of immune function was validated by the identification of novel μ and δ opioid receptors on circulating leukocytes. The novel μ3 opioid receptor subtype has been characterized as an opioid peptide-insensitive and opiate alkaloid-selective G protein-coupled receptor (GPCR) that is functionally linked to the activation of constitutive nitric oxide synthase (cNOS). Opioid peptides stimulate granulocyte and immunocyte activation and chemotaxis via activation of a novel leukocyte δ2 receptor subtype. However, opiate alkaloid μ3 receptor agonists inhibit these same cellular activities. Opiate coupling to cNOS and subsequent production and release of mitochondrial nitric oxide (NO) suggests an evolutionary linkage to similar physiological events in prokaryotic cells. A subpopulation of immunocytes from Mytilus edulis and Leucophaea maderae and human granulocytes respond to low opioid concentrations, mediated by the adherence-promoting role of (D-Ala2-D-Met5)-enkephalinamide (DAMA), which is blocked by naloxone in a dose-dependent manner. Neutral endopeptidase 24.11 (NEP), or enkephalinase (CD10), is present on both human and invertebrate immunocytes. Alkaloids, including morphine, are found in both prokaryotic and eukaryotic cells and may have evolved much later in evolution through horizontal gene transfer. It is possible that opioid-mediated regulatory activities were conserved and elaborated during evolution as the central nervous system (CNS) became immunologically isolated by the blood-brain barrier. Thus, opioid receptor coupling became significant for cognitive and behavioural processes. Although opioid peptides and alkaloids work synergistically to suppress nociception, they mediate different actions in immune surveillance. Increased understanding of the evolutionary development of opioid receptors, nociceptive and anti-nociceptive pathways, and immunomodulation may help in the understanding of the development of tolerance to the clinical use of opiates for pain management. The significance of endogenous morphine's importance to evolution can be ascertained by the number of physiological tissues and systems that can be affected by this chemical messenger mechanism, which transcends pain. An integrated review is presented of opioid and opiate receptors, immunomodulation, and pain associated with inflammation, from an evolutionary perspective.

• MeSH
• biologická evoluce MeSH
• bolest metabolismus   MeSH
• chování MeSH
• imunita MeSH
• imunomodulace MeSH
• lidé MeSH
• morfin metabolismus   MeSH
• opioidní peptidy metabolismus   MeSH
• oxid dusnatý metabolismus   MeSH
• receptory opiátové genetika   metabolismus   MeSH
• zánět metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Neutrophils releasing neutrophil extracellular traps (NETs) infiltrate the pancreas prior to type 1 diabetes (T1D) onset; however, the precise nature of their contribution to disease remains poorly defined. To examine how NETs affect immune functions in T1D, we investigated NET composition and their effect on dendritic cells (DCs) and T lymphocytes in T1D children. We showed that T1D patient NET composition differs substantially from that of healthy donors and that the presence of T1D-NETs in a mixed peripheral blood mononuclear cell culture caused a strong shift toward IFNγ-producing T lymphocytes, mediated through activation of innate immunity cells in T1D samples. Importantly, in a monocyte-derived DC (moDC) culture, NETs induced cytokine production, phenotypic change and IFNγ-producing T cells only in samples from T1D patients but not in those from healthy donors. RNA-seq analysis revealed that T1D-NETs presence causes TGFβ downregulation and IFNα upregulation and creates pro-T1D signature in healthy moDCs.

• MeSH
• buněčná diferenciace MeSH
• dendritické buňky imunologie   MeSH
• diabetes mellitus 1. typu imunologie   MeSH
• dítě MeSH
• dospělí MeSH
• extracelulární pasti imunologie   MeSH
• interferon gama metabolismus   MeSH
• kultivované buňky MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• neutrofily imunologie   MeSH
• přirozená imunita MeSH
• regulace genové exprese MeSH
• rovnováha Th1-Th2 MeSH
• Th1 buňky imunologie   MeSH
• transformující růstový faktor beta metabolismus   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Myeloid cells play a pivotal role in regulating innate and adaptive immune responses. In inflammation, autoimmunity, and after transplantation, myeloid cells have contrasting roles: on the one hand they initiate the immune response, promoting activation and expansion of effector T-cells, and on the other, they counter-regulate inflammation, maintain tissue homeostasis, and promote tolerance. The latter activities are mediated by several myeloid cells including polymorphonuclear neutrophils, macrophages, myeloid-derived suppressor cells, and dendritic cells. Since these cells have been associated with immune suppression and tolerance, they will be further referred to as myeloid regulatory cells (MRCs). In recent years, MRCs have emerged as a therapeutic target or have been regarded as a potential cellular therapeutic product for tolerance induction. However, several open questions must be addressed to enable the therapeutic application of MRCs including: how do they function at the site of inflammation, how to best target these cells to modulate their activities, and how to isolate or to generate pure populations for adoptive cell therapies. In this review, we will give an overview of the current knowledge on MRCs in inflammation, autoimmunity, and transplantation. We will discuss current strategies to target MRCs and to exploit their tolerogenic potential as a cell-based therapy.

• MeSH
• autoimunita * MeSH
• biologické markery MeSH
• homeostáza * MeSH
• homologní transplantace MeSH
• imunofenotypizace MeSH
• imunologická tolerance * MeSH
• imunomodulace MeSH
• lidé MeSH
• makrofágy imunologie   metabolismus   MeSH
• monocyty imunologie   metabolismus   MeSH
• myeloidní buňky imunologie   metabolismus   MeSH
• náchylnost k nemoci MeSH
• neutrofily imunologie   metabolismus   MeSH
• T-lymfocyty - podskupiny imunologie   metabolismus   MeSH
• transplantace orgánů MeSH
• zánět etiologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

In mammals, leptin and tumor-necrosis factor (TNF) are prominent interacting adipokines mediating appetite control and insulin sensitivity. While TNF pleiotropically functions in immune defense and cell survival, leptin is largely confined to signaling energy stores in adipocytes. Knowledge about the function of avian leptin and TNF is limited and they are absent or lowly expressed in adipose, respectively. Employing radiation-hybrid mapping and FISH-TSA, we mapped TNF and its syntenic genes to chicken chromosome 16 within the major histocompatibility complex (MHC) region. This mapping position suggests that avian TNF has a role in regulating immune response. To test its possible interaction with leptin within the immune system and beyond, we compared the transcription patterns of TNF, leptin and their cognate receptors obtained by meta-analysis of GenBank RNA-seq data. While expression of leptin and its receptor (LEPR) were detected in the brain and digestive tract, TNF and its receptor mRNAs were primarily found in viral-infected and LPS-treated leukocytes. We confirmed leptin expression in the duodenum by immunohistochemistry staining. Altogether, we suggest that whereas leptin and TNF interact as adipokines in mammals, in birds, they have distinct roles. Thus, the interaction between leptin and TNF may be unique to mammals.

• MeSH
• buněčné linie MeSH
• duodenum metabolismus   MeSH
• kur domácí genetika   metabolismus   MeSH
• leptin genetika   metabolismus   MeSH
• leptinové receptory metabolismus   MeSH
• mapování chromozomů * MeSH
• mapování pomocí radiačních hybridů MeSH
• messenger RNA genetika   metabolismus   MeSH
• metafáze genetika   MeSH
• receptory TNF genetika   metabolismus   MeSH
• regulace genové exprese * MeSH
• savci genetika   MeSH
• signální transdukce * MeSH
• syntenie genetika   MeSH
• TNF-alfa genetika   metabolismus   MeSH
• trávení * MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• alergologie a imunologie MeSH
• imunitní systém MeSH
• Publikační typ
• učebnice MeSH

• Konspekt
• Patologie. Klinická medicína
• Učební osnovy. Vyučovací předměty. Učebnice
• NLK Obory
• alergologie a imunologie

Genome-wide and candidate gene studies for pulmonary sarcoidosis have highlighted several candidate variants among different populations. However, the genetic basis of functional rare variants in sarcoidosis still needs to be explored. To identify functional rare variants in sarcoidosis, we sequenced exomes of 22 sarcoidosis cases from six families. Variants were prioritized using linkage and high-penetrance approaches, and filtered to identify novel and rare variants. Functional networking and pathway analysis of identified variants was performed using gene ontology based gene-phenotype, gene-gene, and protein-protein interactions. The linkage (n = 1007-7640) and high-penetrance (n = 11,432) prioritized variants were filtered to select variants with (a) reported allele frequency < 5% in databases (1.2-3.4%) or (b) novel (0.7-2.3%). Further selection based on functional properties and validation revealed a panel of 40 functional rare variants (33 from linkage region, 6 highly penetrant and 1 shared by both approaches). Functional network analysis implicated these gene variants in immune responses, such as regulation of pro-inflammatory cytokines including production of IFN-γ and anti-inflammatory cytokine IL-10, leukocyte proliferation, bacterial defence, and vesicle-mediated transport. The KEGG pathway analysis indicated inflammatory bowel disease as most relevant. This study highlights the subsets of functional rare gene variants involved in pulmonary sarcoidosis, such as, regulations of calcium ions, G-protein-coupled receptor, and immune system including retinoic acid binding. The implicated mechanisms in etiopathogenesis of familial sarcoidosis thus include Wnt signalling, inflammation mediated by chemokine and cytokine signalling and cadherin signalling pathways.

• MeSH
• celogenomová asociační studie MeSH
• exom * MeSH
• fenotyp MeSH
• genetická predispozice k nemoci * MeSH
• genetická variace * MeSH
• genetické markery * MeSH
• genotyp MeSH
• genové regulační sítě * MeSH
• lidé MeSH
• plicní sarkoidóza genetika   patologie   MeSH
• rodokmen MeSH
• sekvenční analýza DNA metody   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The adenylate cyclase toxin (CyaA) of the whooping cough agent Bordetella pertussis subverts immune functions of host myeloid cells expressing the αMβ2 integrin (CD11b/CD18, CR3 or Mac-1). CyaA delivers into cytosol of cells an extremely catalytically active adenylyl cyclase enzyme, which disrupts the innate and adaptive immune functions of phagocytes through unregulated production of the key signaling molecule cAMP. We have used phosphoproteomics to analyze cAMP signaling of CyaA in murine bone marrow-derived dendritic cells. CyaA action resulted in alterations of phosphorylation state of a number of proteins that regulate actin cytoskeleton homeostasis, including Mena, Talin-1 and VASP. CyaA action repressed mTOR signaling through activation of mTORC1 inhibitors TSC2 and PRAS40 and altered phosphorylation of multiple chromatin remodelers, including the class II histone deacetylase HDAC5. CyaA toxin action further elicited inhibitory phosphorylation of SIK family kinases involved in modulation of immune response and provoked dephosphorylation of the transcriptional coactivator CRTC3, indicating that CyaA-promoted nuclear translocation of CRTC3 may account for CyaA-induced IL-10 production. These findings document the complexity of subversive physiological manipulation of myeloid phagocytes by the CyaA toxin, serving in immune evasion of the pertussis agent.

• MeSH
• AMP cyklický metabolismus   MeSH
• Bordetella pertussis metabolismus   MeSH
• cytoskeletální proteiny metabolismus   MeSH
• dendritické buňky metabolismus   MeSH
• fosfoproteiny metabolismus   MeSH
• histondeacetylasy metabolismus   MeSH
• mikrofilamentové proteiny metabolismus   MeSH
• molekuly buněčné adheze metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• pertuse mikrobiologie   MeSH
• signální transdukce fyziologie   MeSH
• talin metabolismus   MeSH
• transkripční faktory metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH