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• Potential interplay between sepsis and multiple sclerosis (MS) is reviewed. • Immunological mechanism(s) governing sepsis/MS interactions are proposed. • The role of gut microbiota influencing the sepsis/MS interaction is discussed. Sepsis is a life-threatening condition characterized by an acute cytokine storm followed by prolonged dysfunction of the immune system in the survivors. Post-septic lymphopenia and functional deficits of the remaining immune cells lead to increased susceptibility to secondary infections and other morbid conditions causing late death in the patients. This state of post-septic immunoparalysis may also influence disorders stemming from inappropriate or overactive immune responses, such as autoimmune and immunoinflammatory diseases, including multiple sclerosis. In addition, ongoing autoimmunity likely influences the susceptibility to and outcome of sepsis. This review article addresses the bidirectional relationship between sepsis and multiple sclerosis, with a focus on the immunologic mechanisms of the interaction and potential directions for future studies. [ABSTRACT FROM AUTHOR]

The main aim of this article is to present vaccination as an important factor in the relationship between humans and microorganisms, as well as to emphasize that knowledge about that relationship is significant for generating efficient vaccines. The co-evolution of humans and pathogenic microorganisms is a long-lasting dynamic process. In the course of this relationship some of these microorganisms have had detrimental effects on human populations, while some have adjusted to the host and are now considered beneficial. If we think about the time period of this co-evolution, vaccination has only recently been introduced as a novel factor in the relationship. Not only is it novel, it is also revolutionary in its nature. Thanks to vaccination, numerous diseases caused by pathogenic microorganisms may be eradicated. Vaccination is a powerful man-made selective pressure. This article deals with the co-evolution between microorganisms and humans, with the revolution involved in it, and explains how these reflect on different perspectives of human life. Conclusion. Vaccination, as a revolutionary approach in the co-evolution of humans and pathogenic microorganisms, must be designed carefully for each of the pathogens. Thus, a better understanding of our co-evolution with pathogenic microorganisms, at both genetic and physiological levels, is necessary for designing improved vaccination strategies. [ABSTRACT FROM AUTHOR]

Ethyl pyruvate (EP) is a redox-active compound that has been previously shown to be effective in restraining immune hyperactivity in animal models of various autoimmune and chronic inflammatory diseases. Importantly, EP has also been proven to have a potent tolerogenic effect on dendritic cells (DCs). Here, the influence of EP on the signaling pathways in DCs relevant for their tolerogenicity, including anti-inflammatory NRF2 and pro-inflammatory NF-κB, was explored. Specifically, the effects of EP on DCs obtained by GM-CSF-directed differentiation of murine bone marrow precursor cells and matured under the influence of lipopolysaccharide (LPS) were examined via immunocytochemistry and RT-PCR. EP counteracted LPS-imposed morphological changes and down-regulated the LPS-induced expression of pro-inflammatory mediators in DCs. While it reduced the activation of NF-κB, EP potentiated NRF2 and downstream antioxidative molecules, thus implying the regulation of NRF2 signaling pathways as the major reason for the tolerizing effects of EP on DCs. [ABSTRACT FROM AUTHOR]

Experimental autoimmune encephalomyelitis (EAE) induced in inbred rodents, i.e., genetically identical animals kept under identical environmental conditions, shows variable clinical outcomes. We investigated such variations of EAE in Dark Agouti rats immunized with spinal cord homogenate and identified four groups: lethal, severe, moderate, and mild, at day 28 post immunization. Higher numbers of CD4+ T cells, helper T cells type 1 (Th1) and 17 (Th17) in particular, were detected in the spinal cord of the severe group in comparison with the moderate group. In addition, increased proportion of Th1 and Th17 cells, and heightened levels of interferon (IFN)-γ and interleukin (IL)-6 were detected in the small intestine lamina propria of the severe group. A selective agonist of free fatty acid receptor type 2 (Ffar2) applied orally in the inductive phase of EAE shifted the distribution of the disease outcomes towards milder forms. This effect was paralleled with potentiation of intestinal innate lymphoid cells type 3 (ILC3) regulatory properties, and diminished Th1 and Th17 cell response in the lymph nodes draining the site of immunization. Our results suggest that different clinical outcomes in DA rats are under determinative influence of intestinal ILC3 activity during the inductive phase of EAE. [ABSTRACT FROM AUTHOR]

Gallic acid is a phenolic acid present in various plants, nuts, and fruits. It is well known for its anti-oxidative and anti-inflammatory properties. The phenethyl ester of gallic acid (PEGA) was synthesized with the aim of increasing the bioavailability of gallic acid, and thus its pharmacological potential. Here, the effects of PEGA on encephalitogenic cells were examined, and PEGA was found to modulate the inflammatory activities of T cells and macrophages/microglia. Specifically, PEGA reduced the release of interleukin (IL)-17 and interferon (IFN)-γ from T cells, as well as NO, and IL-6 from macrophages/microglia. Importantly, PEGA ameliorated experimental autoimmune encephalomyelitis, an animal model of chronic inflammatory disease of the central nervous system (CNS)—multiple sclerosis. Thus, PEGA is a potent anti-inflammatory compound with a perspective to be further explored in the context of CNS autoimmunity and other chronic inflammatory disorders. [ABSTRACT FROM AUTHOR]

• PERA ameliorates EAE. • PERA inhibits IFN-γ and IL-17 release. • PERA inhibits NO production. • PERA exhibits anti-encephalitogenic effects. Rosmarinic acid is a polyphenolic compound, abundantly present in herbs of the Lamiaceae family. The aim of the study was to evaluate the immunomodulatory properties of a recently developed phenethyl ester derivative of rosmarinic acid (PERA), with enhanced ability of diffusion through biological membranes, in an animal model of the central nervous system (CNS) autoimmunity. To this end, experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis was used. Daily subcutaneous administration of PERA (30 mg/kg) from day 7 to day 22 after immunization successfully ameliorated EAE induced in Dark Agouti rats, shortening the disease duration and reducing maximal, cumulative and mean clinical score. PERA efficiently reduced production of major encephalitogenic cytokines, interferon (IFN)-γ and interleukin (IL)-17, in immune cells from the CNS or the lymph nodes draining the site of immunization of EAE rats, as well as in CD4+ T cells purified from the lymph nodes. Also, PERA inhibited NO production in the CNS and the lymph nodes, as well as in macrophages and microglial cells. Finally, microglial ability to produce pro-inflammatory cytokines IL-6, and tumor necrosis factor (TNF) were also reduced by PERA. Our results clearly imply that PERA possesses anti-encephalitogenic properties. Thus, further studies on the relevance of the observed effects for the therapy of multiple sclerosis are warranted. [ABSTRACT FROM AUTHOR]

• EAE was induced in DA rats with spinal cord homogenate without adjuvant. • Reactivity of T and B cells to MBP, MOG, and β-synuclein was detected. • T cell infiltration was observed in pons, cerebellum, hippocampus, and cortex. • Immunization led to increase in anxiety-related parameters in rats. We have recently characterized experimental autoimmune encephalomyelitis (EAE) induced in DA rats with spinal cord homogenate without complete Freund's adjuvant (CFA). The main advantage of this multiple sclerosis model is the lack of CFA-related confounding effects which represent the major obstacles in translating findings from EAE to multiple sclerosis. Here, antigen specificity of the cellular and humoral immune response directed against the central nervous system was explored. The reactivity of T and B cells to myelin basic protein, myelin oligodendrocyte glycoprotein, and β-synuclein was detected. Having in mind that reactivity against β-synuclein was previously associated with autoimmunity against the brain, the infiltration of immune cells into different brain compartments, i.e. pons, cerebellum, hippocampus, and cortex was determined. T cell infiltration was observed in all structures examined. This finding stimulated investigation of the effects of immunization on DA rat behavior using the elevated plus maze and the open field test. Rats recovered from EAE displayed increased anxiety-like behavior. These data support CFA-free EAE in DA rats as a useful model for multiple sclerosis research. [Display omitted] [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) became a focus of intensive research due to its death toll during the Covid-19 pandemic. An uncontrolled and excessive inflammatory response mediated by proinflammatory molecules such as high mobility group box protein 1 (HMGB1), IL-6, and TNF mounts as a response to infection. In this study, ethyl pyruvate (EP), a known inhibitor of HMGB1, was tested in the model of murine ARDS induced in C57BL/6 mice by intranasal administration of polyinosinic:polycytidylic acid (poly(I:C)). Intraperitoneal administration of EP ameliorated the ARDS-related histopathological changes in the lungs of poly(I:C)-induced ARDS and decreased numbers of immune cells in the lungs, broncho-alveolar lavage fluid and draining lymph nodes (DLN). Specifically, fewer CD8+ T cells and less activated CD4+ T cells were observed in DLN. Consequently, the lungs of EP-treated animals had fewer damage-inflicting CD8+ cells and macrophages. Additionally, the expression and production of proinflammatory cytokines, IL-17, IFN-γ and IL-6 were downregulated in the lungs. The expression of chemokine CCL5 which recruits immune cells into the lungs was also reduced. Finally, EP downregulated the expression of HMGB1 in the lungs. Our results imply that EP should be further evaluated as a potential candidate for ARDS therapy. • EP treatment attenuates ARDS symptoms in poly(I:C)-treated mice. • Effector immune cells are less abundant in the DLN and lungs of EP-treated animals. • EP treatment reduces the expression and production of proinflammatory cytokines. • HMGB1 expression is downregulated in the lungs of EP-treated mice. [ABSTRACT FROM AUTHOR]

Ethyl pyruvate (EP) has potent influence on redox processes, cellular metabolism, and inflammation. It has been intensively studied in numerous animal models of systemic and organ-specific disorders whose pathogenesis involves a strong immune component. Here, basic chemical and biological properties of EP are discussed, with an emphasis on its redox and metabolic activity. Further, its influence on myeloid and T cells is considered, as well as on intracellular signaling beyond its effect on immune cells. Also, the effects of EP on animal models of chronic inflammatory and autoimmune disorders are presented. Finally, a possibility to apply EP as a treatment for such diseases in humans is discussed. Scientific papers cited in this review were identified using the PubMed search engine that relies on the MEDLINE database. The reference list covers the most important findings in the field in the past twenty years. [ABSTRACT FROM AUTHOR]

Background/Aim: The aim of this study was to compare plasma and urine transforming growth factor-β1 (TGF-β1) levels in patients with different stages of Balkan endemic nephropathy (BEN) with those in patients with primary glomerulonephritis (GN) and healthy controls. Methods: The study involved 47 patients with BEN (30 with manifest BEN and 17 in the early stage of BEN), 12 patients with GN and 10 healthy controls. Plasma and urine TGF-β1 was assayed by enzyme-linked immunosorbent assay. Results: The median plasma TGF-β1 levels differed nonsignificantly between the groups (4,908–6,442 pg/ml), but individual plasma TGF-β1 levels in BEN patients exhibited the highest dispersion. Median urinary TGF-β1 excretion (pg/mg creatinine) was significantly higher in patient groups (manifest BEN: 203, early-stage BEN: 341, GN: 775) than in healthy controls (42). No correlation was found between plasma and urine TGF-β1 levels or between plasma TGF-β1 levels and creatinine clearance for any of the examined groups. Conclusion: Plasma TGF-β1 levels in BEN patients extended over the widest range, but no significant differences were found between the median values for the groups. Median urinary TGF-β1 excretion was significantly higher in patients with BEN and GN than in healthy controls. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Significance: Autoimmune diseases are progressively affecting westernized societies, as the proportion of individuals suffering from autoimmunity is steadily increasing over the past decades. Understanding the role of reactive oxygen species (ROS) in modulation of the immune response in the pathogenesis of autoimmune disorders is of utmost importance. The focus of this review is the regulation of ROS production within tolerogenic dendritic cells (tolDCs) and regulatory T (Treg) cells that have the essential role in the prevention of autoimmune diseases and significant potency in their therapy. Recent Advances: It is now clear that ROS are extremely important for the proper function of both DC and T cells. Antigen processing/presentation and the ability of DC to activate T cells depend upon the ROS availability. Treg differentiation, suppressive function, and stability are profoundly influenced by ROS presence. Critical Issues: Although a plethora of results on the relation between ROS and immune cells exist, it remains unclear whether ROS modulation is a productive way for skewing T cells and DCs toward a tolerogenic phenotype. Also, the possibility of ROS modulation for enhancement of regulatory properties of DC and Treg during their preparation for use in cellular therapy has to be clarified. Future Directions: Studies of DC and T cell redox regulation should allow for the improvement of the therapy of autoimmune diseases. This could be achieved through the direct therapeutic application of ROS modulators in autoimmunity, or indirectly through ROS-dependent enhancement of tolDC and Treg preparation for cell-based immunotherapy. Antioxid. Redox Signal. 34, 364–382. [ABSTRACT FROM AUTHOR]

• MIF is a cytokine, chemokine, enzyme, chaperone and a hormone. • MIF is essential for proper insulin conformation in pancreatic beta cells. • By stimulating inflammation, MIF contributes to insulin resistance. • MIF and its homologue D-dopachrome tautomerase (D-DT) share similar features. • To date, D-DT actions has not been linked to insulin function. Pro-inflammatory nature of macrophage migration inhibitory factor (MIF) has been generally related to the propagation of inflammatory and autoimmune diseases. But this molecule possesses many other peculiar functions, unrelated to the immune system, among which is its supportive role in the post-translational modifications of insulin. In this way MIF enables proper insulin conformation within the pancreatic beta cell and its full activity. The inherent or acquired changes in MIF expression might therefore lead to different insulin processing and initiation of autoimmunity. The relation between MIF and insulin does not stop at this point; these two molecules continue to interact during pathological states characterized by inflammation and insulin resistance. In this context, MIF indirectly and negatively influences insulin action by boosting inflammatory environment and disabling target cells to respond to insulin. On the other side, insulin might interfere with MIF action as well, acting as an anti-inflammatory mediator. Therefore, the proper interaction between MIF and insulin is crucial for maintaining homeostasis, while anti-inflammatory therapies based on the systemic MIF blockage may disturb this balance. This review covers MIF-insulin relationship in the physiological and pathological conditions and discusses the approaches for MIF inhibition and their net effect specifically considering possible impact on insulin misfolding and the possible misinterpretation of previous results due to the discovery of MIF functional homolog D-dopachrome tautomerase. [ABSTRACT FROM AUTHOR]

Dendritic cells (DC) are responsible for the initiation and shaping of the adaptive immune response and are in the focus of autoimmunity research. We were interested in comparison of DC obtained from autoimmunity-prone Dark Agouti (DA) rats and autoimmunity-resistant Albino Oxford (AO) rats. DC were generated from bone marrow precursors and matured (mDC) by lipopolysaccharide. Tolerogenic DC (tolDC) obtained by vitamin D3 treatment were studied in parallel. Profile of cytokine production was different in AO and DA mDC and tolDC. Expression of MHC class II molecules and CD86 were higher in DA DC, while vitamin D3 reduced their expression in dendritic cells of both strains. Allogeneic proliferation of CD4+ T cells was reduced by AO tolDC, but not with DA tolDC in comparison to respective mDC. Finally, expression of various genes identified as differentially expressed in human mDC and tolDC was also analyzed in AO and DA DC. Again, AO and DA DC differed in the expression of the analyzed genes. To conclude, AO and DA DC differ in production of cytokines, expression of antigen presentation-related molecules and in regulation of CD4+ T proliferation. The difference is valuable for understanding the divergence of the strains in their susceptibility to autoimmunity. [ABSTRACT FROM AUTHOR]

C57BL/6, BALB/c and NOD mice are among the most frequently used strains in autoimmunity research. NOD mice spontaneously develop type 1 diabetes (T1D) and they are prone to induction of experimental autoimmune encephalomyelitis (EAE). Both diseases can be routinely induced in C57BL/6 mice, but not in BALB/c mice. Also, C57BL/6 mice are generally considered T helper (Th)1-biased and BALB/c Th2-biased mice. Having in mind increasingly appreciated role of gut associated lymphoid tissue (GALT) cells in autoimmunity, especially in relation to gut Th17 and regulatory T (Treg) cells, our aim was to determine if there are differences in proportion of CD4 + T cell populations in mesenteric lymph nodes and Peyer’s patches of these mouse strains. Lower proportion of Treg was observed in NOD PP, Th2 cells dominated in BALB/c mice in mesenteric lymph nodes (MLN) and Peyer’s patches (PP), while Th1 cells prevailed in C57BL/6 MLN. Intradermal immunization of mice with complete Freund’s adjuvant resulted in significant difference in Th cell distribution in GALT of NOD mice. Differences were less pronounced in C57BL/6 mice, while GALT of BALB/c mice was almost unresponsive to the immunization. The observed strain- and tissue-dependent changes in Treg proportion after the immunization was probably a consequence of different CCR2 or CCR6-related migration patterns and/or in situ Treg proliferation. In conclusion, NOD, a highly autoimmunity-prone mouse strain, exhibits more profound GALT-related immune response upon immunization compared to the strains that are less prone to autoimmunity. [ABSTRACT FROM AUTHOR]

The extracellular matrix glycoprotein tenascin-C (TnC) has been increasingly appreciated as a molecule susceptibly reacting to abnormalities in the mammalian immune system. TnC expression is elevated in inflamed tissues outside the immune system, but also in lymphoid organs. It participates in the promotion of inflammatory responses. Here, the role of TnC in a paradigm of CNS autoimmunity was investigated. Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, was induced in mice deficient in TnC (TnC −/− mice). Amelioration of EAE was observed in these mice in comparison to their wild-type (TnC +/+ ) littermates. Since T helper (Th)1 and Th17 cells play a dominant role in the pathogenesis of EAE, these cells were investigated in addition to analyzing locomotor functions and pro-inflammatory cytokine levels. Smaller numbers of interferon-gamma-producing Th1 cells and reduced ability of Th17 cells to produce interleukin-17 were observed in spleens of TnC −/− mice challenged by immunization with the myelin associated glycoprotein (MOG) when compared to TnC +/+ mice. There was no difference in Th1 and Th17 responses in non-immunized TnC −/− and TnC +/+ mice, thus excluding generalized immunosuppression in TnC −/− mice. These results show that TnC is important for the pathogenesis of CNS autoimmunity and that its deficiency interferes with Th1 and Th17 encephalitogenic potentials. [ABSTRACT FROM AUTHOR]

Background: The mutant CCR5Δ32 allele confers resist- ance to HIV infection. Several hypotheses regarding its ori- gin and persistence in the human population have been proposed. It is assumed that the Δ32 mutation was intro- duced in Northern or Eastern Europe and that it spread to the south. Although the frequency of CCR5Δ32 was deter- mined in numerous European nations and regions, further data are needed to complete the puzzle of CCR5Δ32 dis- tribution within the continent. Methods: To this end, CCR5Δ32 frequency was determined in a Serbian population (sample size 352). DNA was extracted from peripheral whole blood and polymerase chain reaction specific for CCR5 gene was performed. A reaction product of 263 bp was obtained from the wild- -type CCR5 sequence and a product of 231 bp was ob- tained from the truncated CCR5Δ32 sequence. Results: Overall allele frequency of CCR5Δ32 is 4.55%; 0.57% of individuals in the examined population are homo- zygous and 8.52% are heterozygous for CCR5Δ32. Conclusions: The determined frequency of the CCR5Δ32 allele in a Serbian population is unexpectedly low, consid- ering ethnically related populations. Keywords: CCR5, Δ32, Serbia. [ABSTRACT FROM AUTHOR]

Abstract: Most chemotherapeutics harm normal cells causing severe side effects and induce the development of resistance in cancer cells. Antimicrobial peptides (AMPs), recognized as anti-cancer agents, may overcome these limitations. The most studied mechanism underlying multi-drug resistance (MDR) is the over-expression of cell membrane transporter P-glycoprotein (P-gp), which extrudes a variety of hydrophobic drugs. Additionally, P-gp contributes to cell membrane composition and increases the net negative charge on cell surface. We postulated that NK-lysin derived cationic peptide NK-2 might discriminate and preferentially eliminate P-gp over-expressing cancer cells. To test this hypothesis, we employed MDR non-small cell lung carcinoma (NCI-H460/R) and colorectal carcinoma (DLD1-TxR) cell lines with high P-gp expression. MDR cancer cells that survived NK-2 treatment had decreased P-gp expression and were more susceptible to doxorubicin. We found that NK-2 more readily eliminated P-gp high-expressing cells. Acting in ‘carpet-like’ manner NK-2 co-localized with P-gp on the MDR cancer cell membrane. The inhibition of P-gp reduced the NK-2 effect in MDR cancer cells and, vice versa, NK-2 decreased P-gp transport activity. In conclusion, NK-2 could modulate MDR in unique way, eliminating the P-gp high-expressing cells from heterogeneous cancers and making them more vulnerable to classical drug treatment. [Copyright &y& Elsevier]

Abstract: This paper focuses on the synthesis, characterization and biological activity of new N,N′-methylene modified cyclohexyl ethylenediamine-N,N′-diacetate (edda)-type ligands and their Pt(IV) complexes. Both the ligands and complexes were characterized by infrared, UV–vis, ESI-MS, 1D (1H, 13C, 195Pt) and 2D (COSY, HSQC, HMBC) NMR spectroscopy and elemental analysis. The possible correlation between the reduction potentials and the cytotoxicity of the complexes was examined. The potential antitumoral activity of all compounds was tested in vitro on human melanoma A375, human glioblastoma U251, human prostate cancer PC3, human colon cancer HCT116, mouse melanoma B16 and mouse colon cancer CT26CL25 cells, as well as primary fibroblasts and keratinocytes. The results obtained revealed strong antitumor potential of the newly synthesized drugs with preserved efficacy against cisplatin resistant lines and less toxicity towards nonmalignant counterparts. The mechanism found to be responsible for the observed tumoricidal action of each synthesized compound was induction of apoptosis generally accompanied with caspase activation. Taken together, the effective response to the treatment of a wide range of different cell lines, including cisplatin resistant subclones, as well as induction of apoptosis, as the mechanism suggested to be the most desirable way of eliminating malignant cells, represents a great advantage of this novel group of drugs in comparison to other members in this metallo-drug family. [Copyright &y& Elsevier]

Ethyl pyruvate (EP) has profound anti-inflammatory and immunomodulatory properties. Here, its effects were determined on experimental autoimmune myocarditis (EAM) induced in mice by heart-specific myosin-alpha heavy chain peptide immunization. EP was applied intraperitoneally, daily, starting with the immunization. Severity of EAM was determined by histological assessment of immune cell infiltrates into the heart. Cells were phenotypically characterized by flow cytometry. Concentration of cytokines in cell culture supernatants and sera was determined by ELISA. EP reduced the infiltration of immune cells into the heart and lessened heart inflammation. Smaller number of total immune cells, as well as of CD11b+ and CD11c+ cells were isolated from the hearts of EP-treated mice. A reduced number of antigen-presenting cells, detected by anti-CD11c, MHC class II and CD86 antibodies, as well as of T helper (Th)1 and Th17 cells, detected by anti-CD4, IFN-γ and IL-17 antibodies, was determined in mediastinal lymph nodes draining the heart, in parallel. In the spleen, only the number of CD11c+ cells were reduced, but not of the other examined populations, thus implying limited systemic effect of EP. Reduced production of IFN-γ and IL-17 by myosin-alpha heavy chain peptide-restimulated cells of the lymph nodes draining the site of immunization was observed in EP-treated mice. Our results clearly imply that EP restrains autoimmunity in EAM. Therapeutic application of EP in the treatment of myocarditis in humans should be addressed in the forthcoming studies. [ABSTRACT FROM AUTHOR]

Experimental autoimmune encephalomyelitis (EAE) is classically induced with complete Freund's adjuvant (CFA). The immune response against CFA has a confounding influence on the translational capacity of EAE as a multiple sclerosis model. Here, we compare clinical, cellular and molecular properties between syngeneic spinal cord homogenate (SCH)- and SCH + CFA-immunized Dark Agouti rats. EAE signs were observed earlier and the cumulative clinical score was higher without CFA. Also, a higher number of immune cells infiltrates in the spinal cords was noticed at the peak of EAE without CFA. High spinal cord abundance of CD8+CD11bc+MHC class II+ cells was detected in SCH-immunized rats. Myelin basic protein -specific response can be elicited in the cells from the lymph nodes draining the site of SCH immunization. This CFA-free EAE is a reliable multiple sclerosis model. [Display omitted] • EAE can be efficiently induced in DA rats without CFA. • Spinal cord homogenate induces stronger EAE without CFA than with it. • The higher number of immune cells infiltrates in the spinal cords of no-CFA EAE. • High spinal cord abundance of CD8+CD11bc+MHCclassII+ cells is specific to no-CFA EAE. • CFA-free EAE in DA rats is a reliable and replicable multiple sclerosis animal model. [ABSTRACT FROM AUTHOR]

GYY4137 is a hydrogen sulfide (H2S) donor that has been shown to act in an anti-inflammatory manner in vitro and in vivo. Microglial cells are among the major players in immunoinflammatory, degenerative, and neoplastic disorders of the central nervous system, including multiple sclerosis, Parkinson's disease, Alzheimer's disease, and glioblastoma multiforme. So far, the effects of GYY4137 on microglial cells have not been thoroughly investigated. In this study, BV2 microglial cells were stimulated with interferon-gamma and lipopolysaccharide and treated with GYY4137. The agent did not influence the viability of BV2 cells in concentrations up to 200 μM. It inhibited tumor necrosis factor but not interleukin-6 production. Expression of CD40 and CD86 were reduced under the influence of the donor. The phagocytic ability of BV2 cells and nitric oxide production were also affected by the agent. Surprisingly, GYY4137 upregulated generation of reactive oxygen species (ROS) by BV2 cells. The effect was mimicked by another H2S donor, Na2S, and it was not reproduced in macrophages. Our results demonstrate that GYY4137 downregulates inflammatory properties of BV2 cells but increases their ability to generate ROS. Further investigation of this unexpected phenomenon is warranted. [ABSTRACT FROM AUTHOR]