Regulation Of Cytokine Release Research Articles

Pathophysiological, immunogenetic, anatomopathological profile of thrombophilia in pregnancy.

Thrombophilic states have been associated with early and/or late pregnancy loss and possibly other severe obstetrical complications. Pregnancy-induced hypercoagulability, increased stasis, and the consequences of inherited and acquired thrombophilia are just a few of the factors that contribute to the development of thrombosis in pregnancy. In this review, we illustrate the impact that these factors have on the development of thrombophilia during pregnancy. We also explore how thrombophilia impact pregnancy outcomes. Next, we discuss how human leukocyte antigen G plays a part in thrombophilia during pregnancy by regulating cytokine release to prevent trophoblastic cell invasion and maintain local immunotolerance constant. Human leukocyte antigen class E is briefly explored with thrombophilia in pregnancy. Regarding the anatomopathologic aspect, we describe the different histopathological lesions of the placenta found in women with thrombophilia.

In-vitro and in-vivo evaluation and anti-colitis activity of esculetin-loaded nanostructured lipid carrier decorated with DSPE-MPEG2000

Objective Encapsulation of esculetin into DSPE-MPEG2000 carrier was performed to improve its water solubility and oral bioavailability, as well as enhance its anti-inflammatory effect on a mouse model of ulcerative colitis that was induced with dextran sulphate sodium (DSS). Methods We determined the in-vitro and in-vivo high-performance liquid chromatographic (HPLC) analysis method of esculetin; Esculetin-loaded nanostructure lipid carrier (Esc-NLC) was prepared using a thin-film dispersion method, wherein a particle size analyser was used to measure the particle size (PS) and zeta potential (ZP) of the Esc-NLC, while a transmission electron microscope (TEM) was employed to observe its morphology. Also, HPLC was used to measure its drug loading (DL), encapsulation efficiency (EE) and the in-vitro release of the preparation, as well as investigate the pharmacokinetic parameters. In addition, its anti-colitis effect was evaluated via histopathological examination of HE-stained sections and detection of the concentrations of tumour necrosis factor-alpha (TNF-α), interleukin (IL)-1 beta (β), and IL-6 in serum with ELISA kits. Results The PS of Esc-NLC was 102.29 ± 0.63 nm with relative standard deviation (RSD) of 1.08% (with poly-dispersity index-PDI of 0.197 ± 0.023), while the ZP was −15.67 ± 1.39 mV with RSD of 1.24%. Solubility of esculetin was improved coupled with prolonged release time. Its pharmacokinetic parameters were compared with that of free esculetin, wherein the maximum concentration of the drug in plasma was increased by 5.5 times. Of note, bioavailability of the drug was increased by 1.7 times, while the half-life was prolonged by 2.4 times. In the anti-colitis efficacy experiment, the mice in Esc and Esc-NLC groups exhibited significantly reduced levels of TNF-α, IL-1β, and IL-6 in their sera comparable to the DSS group. Colon histopathological examination revealed that mice with ulcerative colitis in both Esc and Esc-NLC groups displayed improved inflammation, amid the Esc-NLC groups having the best prophylactic treatment effect. Conclusion Esc-NLC could ameliorate DSS-induced ulcerative colitis by improving bioavailability, prolonging drug release time and regulating cytokine release. This observation confirmed the potential of Esc-NLC to reduce inflammation in ulcerative colitis, albeit the need for follow-up research to verify the application of this strategy to clinical treatment of ulcerative colitis.

Rosa davurica Inhibited Allergic Mediators by Regulating Calcium and Histamine Signaling Pathways

Rosa davurica Pall. exhibits antioxidant, antiviral, and anti-inflammatory properties; however, its pharmacological mechanism in allergy is yet to be understood. This study confirmed the effects of R. davurica Pall. leaf extract (RLE) on allergy as a new promising material. To evaluate the therapeutic potential of RLE against allergy, we investigated the effects of RLE on the regulatory β-hexosaminidase, histamine, histidine decarboxylase (HDC), Ca2+ influx, nitric oxide (NO), and cytokines induced by lipopolysaccharide (LPS) and DNP-IgE/BSA in Raw 264.7 and RBL-2H3 cells. Furthermore, we examined the effects of RLE on the signaling pathways of mitogen-activated protein kinase (MAPK) and Ca2+ pathways. After stimulating Raw 264.7 cells with LPS, RLE reduced the release of inflammatory mediators, such as NO, cyclooxygenase (COX)-2, inducible nitric oxygen synthase (iNOS), interleukin (IL)-1β, -6, and tumor necrosis factor (TNF)-α. Also, RLE reduced the β-hexosaminidase, histamine, HDC, Ca2+ influx, Ca2+ pathways, and phosphorylation of MAPK in DNP-IgE/BSA-stimulated RBL-2H3 cells. Our studies indicated that RLE is a valuable ingredient for treating allergic diseases by regulating cytokine release from macrophages and mast cell degranulation. Consequently, these results suggested that RLE may serve as a possible alternative promising material for treating allergies.

Assessment of serum high mobility group box 1 protein (HMGB1) levels and its change with treatment in patients with manic episode of bipolar disorder

IntroductionThere has been an increasing evidence in recent years that inflammation plays a role in the pathophysiology of bipolar disorder (BD). In addition to central inflammation, systemic immune response is thought to be associated with disease stages and course. HMGB1 protein is a member of damage-associated molecular pattern which plays a role in the regulation of cytokine release and is important for innate immunity. It has been revealed that HMGB1 levels change in many autoimmun and inflammatory diseasesObjectivesOur study was designed to compare serum HMGB1 levels of inpatients with mania and healthy controls as well as analyzing its relationship with other inflammatory markers and disease severity. Another aim of our study is to determine the changes in serum HMGB1 levels before and after treatment in manic patients.MethodsOur study included 35 patients who were hospitalized in our hospital between November 2020 and April 2021, diagnosed with bipolar disorder, manic episode according to DSM-5 criteria, and 35 healthy controls who matched to the patient group in terms of age and gender. The sociodemographic and clinical characteristics data forms of the participants were filled in, and the patients were evaluated with the Young-Mania Rating Scale (YMRS) and the Hamilton Depression Scale (HAM-D). Serum HMGB1, CRP levels and complete blood count values were measured in healthy controls and patients before and after the treatment.ResultsThe main finding of our study is that HMGB1 levels did not show a statistically significant difference in the patient and healthy control groups (p>0.05). In addition, there was no significant change in serum HMGB1 levels of the patients after treatment compared to the level before treatment (p>0.05). Our study has also revealed that manic patients had a higher level of CRP than the ones in control group at a statistically significant level. The platelet/lymphocyte and neutrophil/lymphocyte rates of the patients increased after the treatment compared to the pre-treatment period (respectively p=0,026, p=0,003).ConclusionsThe higher CRP levels in manic patients support the hypothesis of low-grade chronic inflammation, which is thought to be involved in the etiology of BD. The most important finding of this study is that there is no statistically significant difference of serum HMGB1 levels between the two groups. This can be explained by the fact that HMBG1 is one of the late mediators of inflammation and does not rise immediately during the acute period. However, since the inflammation process includes complex mechanisms involving many systems, it makes it difficult to comment on this issue.Disclosure of InterestNone Declared

Enhancement of oral bioavailability and anti-colitis effect of luteolin-loaded polymer micelles with RA (rosmarinic acid)-SS-mPEG as carrier

Objective Polymer micelles were prepared (L-RSPMs) with luteolin and synthetic RA-SS-mPEG polymeric material before evaluation of their anti-inflammatory effect on 2, 4, 6-trinitro-benzene-sulfonic acid (TNBS)-induced ulcerative colitis (UC) model in rats. Methods The synthetic RA-SS-mPEG was characterized with NMR spectroscopy, before preparation of luteolin-coated RA-SS-mPEG polymer micelles. The in vitro characterization and evaluation of the formulation were accomplished, couple with its pharmacokinetic parameters. The levels of PEG2, MDA, CRP and GSH, as well as concentrations of TNF-α, IL1-β, IL-6 and IL-10 in serum and colon tissue were detected via ELISA kit. The degree of colon injury and inflammation was evaluated via histopathologic examination. Results L-RSPMs displayed small average droplet size (133.40 ± 4.52 nm), uniformly dispersed (PDI: 0.163 ± 0.011), good stability, slow release and enhanced solubility. We observed 353.28% increase in the relative bioavailability of L-RSPMs compared to free luteolin, while the half-life of the micelle was extended by 6.16h. Compared to model (M) group, luteolin (low and high doses) and L-RSPMs (low and high doses) significantly reduced levels of MDA, PEG2, CRP, TNF-α, IL-6 and IL-1β in colon tissue and serum of colitic rats but dose dependently increased IL-10 and SOD levels (p < 0.01). Histopathologic examination of colon showed that luteolin (low and high doses) and L-RSPMs (low and high doses) improved colonic inflammation in colitic rats to varying degrees compared to M group. Conclusion L-RSPMs could improve TNBS-induced colon inflammation by enhancing bioavailability, promoting antioxidant effects and regulating cytokine release, which may become a potential agent for UC treatment in clinical settings.

2D and 3D cultured human umbilical cord-derived mesenchymal stem cell-conditioned medium has a dual effect in type 1 diabetes model in rats: immunomodulation and beta-cell regeneration

BackgroundType 1 diabetes (T1D) is a T-cell-mediated autoimmune disease characterized by the irreversible destruction of insulin-producing β-cells in pancreatic islets. Helper and cytotoxic T-cells and cytokine production, which is impaired by this process, take a synergetic role in β-cell destruction, and hyperglycemia develops due to insulin deficiency in the body. Mesenchymal stem cells (MSCs) appear like an excellent therapeutic tool for autoimmune diseases with pluripotent, regenerative, and immunosuppressive properties. Paracrine factors released from MSCs play a role in immunomodulation by increasing angiogenesis and proliferation and suppressing apoptosis. In this context, the study aims to investigate the therapeutic effects of MSC’s secretomes by conditioned medium (CM) obtained from human umbilical cord-derived MSCs cultured in 2-dimensional (2D) and 3-dimensional (3D) environments in the T1D model.MethodsFirst, MSCs were isolated from the human umbilical cord, and the cells were characterized. Then, two different CMs were prepared by culturing MSCs in 2D and 3D environments. The CM contents were analyzed in terms of total protein, IL-4, IL-10, IL-17, and IFN-λ. In vivo studies were performed in Sprague-Dawley-type rats with an autoimmune T1D model, and twelve doses of CM were administered intraperitoneally for 4 weeks within the framework of a particular treatment model. In order to evaluate immunomodulation, the Treg population was determined in lymphocytes isolated from the spleen after sacrification, and IL-4, IL-10, IL-17, and IFN-λ cytokines were analyzed in serum. Finally, β-cell regeneration was evaluated immunohistochemically by labeling Pdx1, Nkx6.1, and insulin markers, which are critical for the formation of β-cells.ResultsTotal protein and IL-4 levels were higher in 3D-CM compared to 2D-CM. In vivo results showed that CMs induce the Treg population and regulate cytokine release. When the immunohistochemical results were evaluated together, it was determined that CM application significantly increased the rate of β-cells in the islets. This increase was at the highest level in the 3D-CM applied group.ConclusionThe dual therapeutic effect of MSC-CM on immunomodulation and homeostasis/regeneration of β-cells in the T1D model has been demonstrated. Furthermore, this effect could be improved by using 3D scaffolds for culturing MSCs while preparing CM.

Alpha-Momorcharin Inhibits Proinflammatory Cytokine Expression by M1 Macrophages but Not Anti-Inflammatory Cytokine Expression by M2 Macrophages.

BackgroundAlpha-momorcharin (α-MMC) is a natural medicine derived from bitter melon and has been found to exert immunomodulatory effects. Our previous study indicated that α-MMC can regulate cytokine release from monocytes, but it remains unknown about its regulatory effect on different types of cytokines, such as inflammatory cytokines or anti-inflammatory cytokines.MethodsLPS-induced M1-type macrophages model and IL-4-induced M2-type macrophages model were established, and the expression of proinflammatory cytokines and anti-inflammatory cytokines were assessed by ELISA after α-MMC was administered. Then, a LPS-induced acute pneumonia mouse model was established, the proinflammatory cytokines levels and inflammatory lesions in lung tissues were examined by ELISA or H&E staining. Furthermore, omics screening analysis and Western blotting verification were performed on TLR4 and JAK1-STAT6 signalling pathway-related proteins to elucidate the regulatory mechanism of α-MMC in those M1 macrophages and M2 macrophages.ResultsAt a noncytotoxic dose of 0.3 μg/mL, α-MMC significantly inhibited the LPS-induced expression of inflammatory cytokines, such as TNF-α, IL-1β, IL-6, IL-8, MIP-1α and MCP-1, by M1 macrophages in a time-dependent manner, but α-MMC did not inhibit the IL-4-induced synthesis of anti-inflammatory cytokines, such as IL-10, IL-1RA, EGF, VEGF, TGF-β and CCL22, by M2 macrophages. Moreover, α-MMC also inhibited inflammatory cytokine expression in an LPS-induced acute pneumonia mouse model and alleviated inflammation in lung tissues. Furthermore, omics screening and Western blotting analysis confirmed that α-MMC inhibited TAK1/p-TAK1 and subsequently blocked the downstream MAPK and NF-κB pathways, thus inhibiting the LPS-induced inflammatory cytokine expression.ConclusionOur results reveal that α-MMC inhibits proinflammatory cytokine expression by M1 macrophages but not anti-inflammatory cytokine expression by M2 macrophages. The efficacy of α-MMC in selectively inhibiting proinflammatory cytokine expression renders it particularly suitable for the treatment of severe inflammation and autoimmune diseases characterized by cytokine storms.

Exploring the role of antibiotics and steroids in managing respiratory diseases

Respiratory diseases (RDs), such as chronic obstructive pulmonary disease, cystic fibrosis, asthma, and pneumonia, are associated with significant morbidity and mortality. Treatment usually consists of antibiotics and steroids. Relevant published literature reviews, studies, and clinical trials were accessed from institutional and electronic databases. The keywords used were respiratory diseases, steroids, antibiotics, and combination of steroids and antibiotics. Selected articles and literature were carefully reviewed. Antibiotics are often prescribed as the standard therapy to manage RDs. Types of causative respiratory pathogens, spectrum of antibiotics activity, route of administration, and course of therapy determine the type of antibiotics that are prescribed. Despite being associated with good clinical outcome, treatment failure and recurrence rate are still high. In addition, antibiotic resistance has been widely reported due to bacterial mutations in response to the use of antibiotics, which render them ineffective. Nevertheless, there has been a growing demand for corticosteroids (CS) and antibiotics to treat a wide variety of diseases, including various airway diseases, due to their immunosuppressive and anti-inflammatory properties. The use of CS is well established and there are different formulations based on the diseases, such as topical administration, tablets, intravenous injections, and inhaled preparations. Both antibiotics and CS possess similar properties in terms of their anti-inflammatory effects, especiallyregulating cytokine release. Thus, the current review examines and discusses the different applications of antibiotics, CS, and their combination in managing various RDs. Drawbacks of these interventions are also discussed.

Ограниченная склеродермия у новорожденного ребенка (случай из практики)

Scleroderma is a rare condition in pediatrics although it ranks third (after juvenile idiopathic arthritis and systemic lupus erythematosus) among rheumatic diseases in children. Congenital scleroderma is considered casuistic since only single case reports are available in publications worldwide. The etiology of congenital scleroderma remains elusive. The principal pathogenic mechanisms are vascular network impairment, immune system dysfunction with abnormal regulation of cytokine release and altered collagen synthesis with fibroblast proliferation and fibrosis. This paper describes a newborn girl with congenital localized nodular scleroderma whose clinical presentations were detected at birth. The authors discuss difficulties with the diagnosis based on clinical and routine lab and instrumental tests. The role of modern morphological studies (given the lack of specific lab tests) to diagnose scleroderma in a newborn is emphasized. Finally, this paper provides a brief review of published data on congenital scleroderma. KEYWORDS: congenital scleroderma, children, diagnostics, differential diagnosis, morphological studies. FOR CITATION: Akhmina N.I., Utkin P.S., Shalatonin M.P. et al. Localized scleroderma in a newborn (case report). Russian Journal of Woman and Child Health. 2022;5(2):169–172 (in Russ.). DOI: 10.32364/2618-8430-2022-5-2-169-172.

Targeting CD38 in acute myeloid leukemia interferes with leukemia trafficking and induces phagocytosis

Targeting the interaction between leukemic cells and the microenvironment is an appealing approach to enhance the therapeutic efficacy in acute myeloid leukemia (AML). AML infiltration induces a significant release of inflammatory cytokines in the human bone marrow niche which accelerates leukemogenesis. As the transmembrane glycoprotein CD38 has been shown to regulate cytokine release, we assessed the anti-leukemic potential of CD38 inhibition in AML. CD38 expression in AML cells proved to depend on microenvironmental cues and could be significantly enforced through addition of tretinoin. In fact, the anti-CD38 antibody daratumumab showed significant cytostatic efficacy in a 3D in vitro triple-culture model of AML, but with modest cell-autonomous cytotoxic activity and independent of CD38 expression level. In line with a predominantly microenvironment-mediated activity of daratumumab in AML, CD38 inhibition significantly induced antibody-dependent phagocytosis and showed interference with AML cell trafficking in vivo in a xenograft transplantation model, but overall lacked robust anti-leukemic effects.

Functional Exploration of Desmarestia ligulate and Anti-inflammatory Activity of Functional Substance D-mannuronic acid

This study was conducted to investigate the anti-inflammatory activity of Desmarestia ligulate (D. ligulate) leaf. The effects on cell viability and anti-inflammatory activities of D. ligulata leaf extract, as well as those of D-mannuronic acid (DMA), on RAW 264.7 cells (macrophages) and peripheral blood mononuclear cells (PBMCs) during inflammation-induced stress were analyzed by determining the levels of NO, IL-17, IL-4, and TNF-α using ELISA and evaluating the expression of iNOS and MPO genes. D. ligulata leaf extract and DMA exhibited low toxicity in RAW 264.7 cells and PBMCs, which secreted lower levels of TNF-α and IL-4. The anti-inflammatory effect of DMA was higher than that of D. ligulata leaf extract as indicated by the levels of the inflammatory cytokine IL-17. Furthermore, treatment with D. ligulata leaf extract and DMA decreased the expression of iNOS and MPO genes after stress induction. These findings suggested that D. ligulata leaf extract and DMA exert anti-inflammatory effects as well as regulate cytokine release activities and inflammatory gene expression. Therefore, D. ligulata leaf extract and DMA may be used as cosmetic materials to control skin inflammation. Keywords: Anti-inflammatory; Desmarestia ligulate; D-mannuronic acid; IL-17; IL-6

Surgical Transplantation of Human RPE Stem Cell-Derived RPE Monolayers into Non-Human Primates with Immunosuppression.

SummaryRecent trials of retinal pigment epithelium (RPE) transplantation for the treatment of disorders such as age-related macular degeneration have been promising. However, limitations of existing strategies include the uncertain survival of RPE cells delivered by cell suspension and the inherent risk of uncontrolled cell proliferation in the vitreous cavity. Human RPE stem cell-derived RPE (hRPESC-RPE) transplantation can rescue vision in a rat model of retinal dystrophy and survive in the rabbit retina for at least 1 month. The present study placed hRPESC-RPE monolayers under the macula of a non-human primate model for 3 months. The transplant was able to recover in vivo and maintained healthy photoreceptors. Importantly, there was no evidence that subretinally transplanted monolayers underwent an epithelial-mesenchymal transition. Neither gliosis in adjacent retina nor epiretinal membranes were observed. These findings suggest that hRPESC-RPE monolayers are safe and may be a useful source for RPE cell replacement therapy.

Multi-omic analysis reveals HIP-55-dependent regulation of cytokines release.

HIP-55 (HPK1 [hematopoietic progenitor kinase 1] -interacting protein of 55 kDa) contains an actin-depolymerizing factor homology (ADF-H) domain at the N-terminus and a src homology 3 (SH3) domain at the C-terminus, which plays an important role in the T cell receptor (TCR) and B-cell receptor (BCR) signaling and immune system. In our previous studies, HIP-55 was found to be highly expressed in several types of tumors and function as a novel oncogenic signaling hub that regulates tumor progression and metastasis through defined functional domains, actin-binding and SH3 modules. However, the wider functions and mechanisms of HIP-55 are still unclear. Here, multi-omic analysis revealed that one of the main biofunctions of HIP-55 is the regulation of cytokines release. Furthermore, to investigate the role of HIP-55 in the cytokine production, a series Cytokine Antibody Arrays were performed to detect differentially expressed cytokines between control and HIP-55 knockdown cells. A total of 97 differentially expressed cytokines were identified from 300 cytokines in A549 cell. Bioinformatics analysis showed these differentially cytokines were mainly enriched in cancer signal pathways and IL-6 is the most critical hub in the integrated network. Analysis of RNAseq data from lung cancer patients showed that there is a strong negative correlation between HIP-55 and interleukin-6 (IL-6) in samples from lung adenocarcinoma patients. Our data indicated that HIP-55 may participate in cancer progression and metastasis via regulating cytokines release.

Functions of acetylcholine-producing lymphocytes in immunobiology.

Recent advances in neuroscience and immunology have shown that cholinergic signals are vital in the regulation of inflammation and immunity. Choline acetyltransferase+ (ChAT+) lymphocytes have the capacity to biosynthesize and release acetylcholine, the cognate ligand for cholinergic receptors. Acetylcholine-producing T cells relay neural signals in the 'inflammatory reflex' that regulate cytokine release in spleen. Mice deficient in acetylcholine-producing T cells have increased blood pressure, show reduced local vasodilatation and viral control in lymphocytic choriomeningitis virus infection, and display changes in gut microbiota compared with littermates. These observations indicate that ChAT+ lymphocytes play physiologically important roles in regulation of inflammation and anti-microbial defense. However, the full scope and importance of ChAT+ lymphocytes in immunity and vascular biology remains to be elucidated. Here, we review key findings in this emerging area.

Role of hydrogen sulfide mediated autophagy related genes in intestinal function injury of sepsis

Sepsis is an organ dysfunction that endangers a patient's life caused by an imbalanced infection response, and is a clinically critical illness. Despite a deep understanding of the pathogenesis of sepsis, there has been no significant improvement in sepsis mortality during clinical treatment at home and abroad. In recent years, the role of autophagy in the pathogenesis of sepsis has become a new research point in the field of medical research. Autophagy may protect the body by removing pathogenic microorganisms, neutralizing microbial toxins, and regulating cytokine release in sepsis. Studies have shown that autophagy plays a role in heart and lung organ dysfunction and inflammatory immune response in sepsis. Studies have also shown that hydrogen sulphide (H2S) can activate autophagy through multiple signaling pathways, such as adenylate-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR), phosphoinositide 3 kinase/Akt/mTOR (PI3K/Akt/mTOR), liver kinase B1/STE20 related adapter protein/mouse protein 25 (LKB1/STRAD/MO25) and microRNA-30c (miR-30c), etc. signaling pathways. This article reviewed the effects of H2S on autophagy-related genes Beclin-1 and microtubule-associated protein light 3 chain (LC3) on intestinal function of sepsis in order to explore the H2S-mediated autophagy gene expression in pus. The protective role of autophagy gene for intestinal dysfunction provides a new strategy for the treatment of sepsis in the future.

Redox Regulation of Cytokine Release in Male and Female Patients with Pulmonary Arterial Hypertension

Redox Regulation of Cytokine Release in Male and Female Patients with Pulmonary Arterial Hypertension

The Establishment and Validation of the Human U937 Cell Line as a Cellular Model to Screen Immunomodulatory Agents Regulating Cytokine Release Induced by Influenza Virus Infection.

Severe influenza infections are often associated with the excessive induction of pro-inflammatory cytokines, which is also referred to as “cytokine storms”. Several studies have shown that cytokine storms are directly associated with influenza-induced fatal acute lung injury and acute respiratory distress syndrome. Due to the narrow administration window, current antiviral therapies are often inadequate. The efforts to use immunomodulatory agents alone or in combination with antiviral agents in the treatment of influenza in animal models have resulted in the achievement of protective effects accompanied with reduced cytokine production. Currently, there are no immunomodulatory drugs for influenza available for clinical use. Animal models, despite being ideal to study the anti-inflammatory responses to influenza virus infection, are very costly and time-consuming. Therefore, there is an urgent need to establish fast and economical screening methods using cell-based models to screen and develop novel immunomodulatory agents. In this study, we screened seven human cell lines and found that the human monocytic cell U937 supports the replication of different subtypes of influenza viruses as well as the production of the important pro-inflammatory cytokines and was selected to develop the cell-based model. The U937 cell model was validated by testing a panel of known antiviral and immunomodulatory agents and screening a drug library consisting of 1280 compounds comprised mostly of FDA-approved drugs. We demonstrated that the U937 cell model is robust and suitable for the high-throughput screening of immunomodulators and antivirals against influenza infection.Electronic supplementary materialThe online version of this article (10.1007/s12250-019-00145-w) contains supplementary material, which is available to authorized users.

Transient Receptor Potential Vanilloid 1 Modulates Central Inflammation in Multiple Sclerosis.

Introduction: Disease course of multiple sclerosis (MS) is negatively influenced by proinflammatory molecules released by activated T and B lymphocytes and local immune cells. The endovanilloid system plays different physiological functions, and preclinical data suggest that transient receptor potential vanilloid type 1 (TRPV1) could modulate neuroinflammation in this disorder.Methods: The effect of TRPV1 activation on the release of two main proinflammatory cytokines, tumor necrosis factor (TNF) and interleukin (IL)-6, was explored in activated microglial cells. Furthermore, in a group of 132 MS patients, the association between the cerebrospinal fluid (CSF) levels of TNF and IL-6 and a single nucleotide polymorphisms (SNP) influencing TRPV1 protein expression and function (rs222747) was assessed.Results: In in vitro experiments, TRPV1 stimulation by capsaicin significantly reduced TNF and IL-6 release by activated microglial cells. Moreover, the anti-inflammatory effect of TRPV1 activation was confirmed by another TRPV1 agonist, the resiniferatoxin (RTX), whose effects were significantly inhibited by the TRPV1 antagonist, 5-iodoresiniferatoxin (5-IRTX). Vice versa, BV2 pre-treatment with 5-IRTX increased the inflammatory response induced by LPS. Moreover, in MS patients, a significant association emerged between TRPV1 SNP rs222747 and CSF TNF levels. In particular, the presence of a G allele, known to result in increased TRPV1 protein expression and function, was associated to lower CSF levels of TNF.Conclusions: Our results indicate that TRPV1 influences central inflammation in MS by regulating cytokine release by activated microglial cells. The modulation of the endovanilloid system may represent a useful approach to contrast neuroinflammation in MS.

P2X7 receptor signaling during adult hippocampal neurogenesis.

Neurogenesis is a persistent and essential feature of the adult mammalian hippocampus. Granular neurons generated from resident pools of stem or progenitor cells provide a mechanism for the formation and consolidation of new memories. Regulation of hippocampal neurogenesis is complex and multifaceted, and numerous signaling pathways converge to modulate cell proliferation, apoptosis, and clearance of cellular debris, as well as synaptic integration of newborn immature neurons. The expression of functional P2X7 receptors in the central nervous system has attracted much interest and the regulatory role of this purinergic receptor during adult neurogenesis has only recently begun to be explored. P2X7 receptors are exceptionally versatile: in their canonical role they act as adenosine triphosphate-gated calcium channels and facilitate calcium-signaling cascades exerting control over the cell via calcium-encoded sensory proteins and transcription factor activation. P2X7 also mediates transmembrane pore formation to regulate cytokine release and facilitate extracellular communication, and when persistently stimulated by high extracellular adenosine triphosphate levels large P2X7 pores form, which induce apoptotic cell death through cytosolic ion dysregulation. Lastly, as a scavenger receptor P2X7 directly facilitates phagocytosis of the cellular debris that arises during neurogenesis, as well as during some disease states. Understanding how P2X7 receptors regulate the physiology of stem and progenitor cells in the adult hippocampus is an important step towards developing useful therapeutic models for regenerative medicine. This review considers the relevant aspects of adult hippocampal neurogenesis and explores how P2X7 receptor activity may influence the molecular physiology of the hippocampus, and neural stem and progenitor cells.

Early-life adversity programs long-term cytokine and microglia expression within the HPA axis in female Japanese quail.

Stress exposure during prenatal and postnatal development can have persistent and often dysfunctional effects on several physiological systems, including immune function, affecting the ability to combat infection. The neuroimmune response is inextricably linked to the action of the hypothalamic-pituitary-adrenal (HPA) axis. Cytokines released from neuroimmune cells, including microglia, activate the HPA axis, while glucocorticoids in turn regulate cytokine release from microglia. Because of the close links between these two physiological systems, coupled with potential for persistent changes to HPA axis activity following developmental stress, components of the neuroimmune system could be targets for developmental programming. However, little is known of any programming effects of developmental stress on neuroimmune function. We investigated whether developmental stress exposure via elevated prenatal corticosterone (CORT) or postnatal unpredictable food availability had long-term effects on pro- (IL-1β) and anti-inflammatory (IL-10) cytokine and microglia-dependent gene (CSF1R) expression within HPA axis tissues in a precocial bird, the Japanese quail (Coturnix japonica). Following postnatal stress, we observed increased IL-1β expression in the pituitary gland, reduced IL-10 expression in the amygdala and hypothalamus, and reduced CSF1R expression within the hypothalamus and pituitary gland. Postnatal stress disrupted the ratio of IL-1β:IL-10 expression within the hippocampus and hypothalamus. Prenatal stress only increased IL-1β expression in the pituitary gland. We found no evidence for interactive or cumulative effects across life stages on basal cytokine and glia expression in adulthood. We show that postnatal stress may have a larger impact than elevated prenatal CORT on basal immunity in HPA-axis-specific brain regions, with changes in cytokine homeostasis and microglia abundance. These results provide evidence for postnatal programming of a pro-inflammatory neuroimmune phenotype at the expense of reduced microglia, which could have implications for central nervous system health and subsequent neuroimmune responses.