Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 55
Filter
1.
Eur J Immunol ; 54(3): e2350664, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38088236

ABSTRACT

COVID-19 is a systemic inflammatory disease initiated by SARS-CoV-2 virus infection. Multiple vaccines against the Wuhan variant of SARS-CoV-2 have been developed including a whole virion beta-propiolactone-inactivated vaccine based on the B.1.1 strain (CoviVac). Since most of the population has been vaccinated by targeting the original or early variants of SARS-CoV-2, the emergence of novel mutant variants raises concern over possible evasion of vaccine-induced immune responses. Here, we report on the mechanism of protection by CoviVac, a whole virion-based vaccine, against the Omicron variant. CoviVac-immunized K18-hACE2 Tg mice were protected against both prototype B.1.1 and BA.1-like (Omicron) variants. Subsequently, vaccinated K18-hACE2 Tg mice rapidly cleared the infection via cross-reactive T-cell responses and cross-reactive, non-neutralizing antibodies recognizing the Omicron variant Spike protein. Thus, our data indicate that efficient protection from SARS-CoV-2 variants can be achieved by the orchestrated action of cross-reactive T cells and non-neutralizing antibodies.


Subject(s)
COVID-19 , Melphalan , SARS-CoV-2 , gamma-Globulins , Animals , Humans , Mice , Vaccines, Inactivated , Antibody Formation , COVID-19/prevention & control , T-Lymphocytes , Virion , Broadly Neutralizing Antibodies , Antibodies, Neutralizing , Antibodies, Viral
2.
Biochemistry (Mosc) ; 89(5): 904-911, 2024 May.
Article in English | MEDLINE | ID: mdl-38880650

ABSTRACT

Multiple sclerosis (MS) is a complex autoimmune disease of central nervous system (CNS) characterized by the myelin sheath destruction and compromised nerve signal transmission. Understanding molecular mechanisms driving MS development is critical due to its early onset, chronic course, and therapeutic approaches based only on symptomatic treatment. Cytokines are known to play a pivotal role in the MS pathogenesis with interleukin-6 (IL-6) being one of the key mediators. This study investigates contribution of IL-6 produced by microglia and dendritic cells to the development of experimental autoimmune encephalomyelitis (EAE), a widely used mouse model of MS. Mice with conditional inactivation of IL-6 in the CX3CR1+ cells, including microglia, or CD11c+ dendritic cells, displayed less severe symptoms as compared to their wild-type counterparts. Mice with microglial IL-6 deletion exhibited an elevated proportion of regulatory T cells and reduced percentage of pathogenic IFNγ-producing CD4+ T cells, accompanied by the decrease in pro-inflammatory monocytes in the CNS at the peak of EAE. At the same time, deletion of IL-6 from microglia resulted in the increase of CCR6+ T cells and GM-CSF-producing T cells. Conversely, mice with IL-6 deficiency in the dendritic cells showed not only the previously described increase in the proportion of regulatory T cells and decrease in the proportion of TH17 cells, but also reduction in the production of GM-CSF and IFNγ in the secondary lymphoid organs. In summary, IL-6 functions during EAE depend on both the source and localization of immune response: the microglial IL-6 exerts both pathogenic and protective functions specifically in the CNS, whereas the dendritic cell-derived IL-6, in addition to being critically involved in the balance of regulatory T cells and TH17 cells, may stimulate production of cytokines associated with pathogenic functions of T cells.


Subject(s)
Dendritic Cells , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental , Interleukin-6 , Microglia , Multiple Sclerosis , Animals , Dendritic Cells/metabolism , Dendritic Cells/immunology , Mice , Interleukin-6/metabolism , Multiple Sclerosis/immunology , Multiple Sclerosis/metabolism , Multiple Sclerosis/pathology , Microglia/metabolism , Encephalomyelitis, Autoimmune, Experimental/metabolism , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , Mice, Inbred C57BL , CX3C Chemokine Receptor 1/metabolism , CX3C Chemokine Receptor 1/genetics , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Receptors, CCR6/metabolism , Receptors, CCR6/genetics , Female
3.
Biochemistry (Mosc) ; 89(5): 817-838, 2024 May.
Article in English | MEDLINE | ID: mdl-38880644

ABSTRACT

In recent years, the role of cellular metabolism in immunity has come into the focus of many studies. These processes form a basis for the maintenance of tissue integrity and homeostasis, as well as represent an integral part of the immune response, in particular, inflammation. Metabolic adaptations not only ensure energy supply for immune response, but also affect the functions of immune cells by controlling transcriptional and post-transcriptional programs. Studying the immune cell metabolism facilitates the search for new treatment approaches, especially for metabolic disorders. Macrophages, innate immune cells, are characterized by a high functional plasticity and play a key role in homeostasis and inflammation. Depending on the phenotype and origin, they can either perform various regulatory functions or promote inflammation state, thus exacerbating the pathological condition. Furthermore, their adaptations to the tissue-specific microenvironment influence the intensity and type of immune response. The review examines the effect of metabolic reprogramming in macrophages on the functional activity of these cells and their polarization. The role of immunometabolic adaptations of myeloid cells in tissue homeostasis and in various pathological processes in the context of inflammatory and metabolic diseases is specifically discussed. Finally, modulation of the macrophage metabolism-related mechanisms reviewed as a potential therapeutic approach.


Subject(s)
Homeostasis , Inflammation , Macrophages , Macrophages/metabolism , Macrophages/immunology , Humans , Inflammation/metabolism , Inflammation/immunology , Animals
4.
Biochemistry (Mosc) ; 89(5): 853-861, 2024 May.
Article in English | MEDLINE | ID: mdl-38880646

ABSTRACT

Tumor necrosis factor (TNF) is one of many cytokines - protein molecules responsible for communication between the cells of immune system. TNF was discovered and given its grand name because of its striking antitumor effects in experimental systems, but its main physiological functions in the context of whole organism turned out to be completely unrelated to protection against tumors. This short review discusses "man-made" mouse models generated by early genome-editing technologies, which enabled us to establish true functions of TNF in health and certain diseases as well as to unravel potential strategies for improving therapy of TNF-dependent diseases.


Subject(s)
Tumor Necrosis Factor-alpha , Animals , Humans , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , Mice , Gene Editing/methods , Neoplasms/immunology , Neoplasms/genetics , Neoplasms/therapy
5.
J Allergy Clin Immunol ; 149(6): 2078-2090, 2022 06.
Article in English | MEDLINE | ID: mdl-34974067

ABSTRACT

BACKGROUND: Infectious agents can reprogram or "train" macrophages and their progenitors to respond more readily to subsequent insults. However, whether such an inflammatory memory exists in type 2 inflammatory conditions such as allergic asthma was not known. OBJECTIVE: We sought to decipher macrophage-trained immunity in allergic asthma. METHODS: We used a combination of clinical sampling of house dust mite (HDM)-allergic patients, HDM-induced allergic airway inflammation in mice, and an in vitro training setup to analyze persistent changes in macrophage eicosanoid, cytokine, and chemokine production as well as the underlying metabolic and epigenetic mechanisms. Transcriptional and metabolic profiles of patient-derived and in vitro trained macrophages were assessed by RNA sequencing or metabolic flux analysis and liquid chromatography-tandem mass spectrometry analysis, respectively. RESULTS: We found that macrophages differentiated from bone marrow or blood monocyte progenitors of HDM-allergic mice or asthma patients show inflammatory transcriptional reprogramming and excessive mediator (TNF-α, CCL17, leukotriene, PGE2, IL-6) responses upon stimulation. Macrophages from HDM-allergic mice initially exhibited a type 2 imprint, which shifted toward a classical inflammatory training over time. HDM-induced allergic airway inflammation elicited a metabolically activated macrophage phenotype, producing high amounts of 2-hydroxyglutarate (2-HG). HDM-induced macrophage training in vitro was mediated by a formyl peptide receptor 2-TNF-2-HG-PGE2/PGE2 receptor 2 axis, resulting in an M2-like macrophage phenotype with high CCL17 production. TNF blockade by etanercept or genetic ablation of Tnf in myeloid cells prevented the inflammatory imprinting of bone marrow-derived macrophages from HDM-allergic mice. CONCLUSION: Allergen-triggered inflammation drives a TNF-dependent innate memory, which may perpetuate and exacerbate chronic type 2 airway inflammation and thus represents a target for asthma therapy.


Subject(s)
Asthma , Hypersensitivity , Animals , Dermatophagoides pteronyssinus , Disease Models, Animal , Humans , Inflammation , Macrophages , Mice , Prostaglandins E/metabolism , Pyroglyphidae
6.
Int J Mol Sci ; 24(9)2023 May 05.
Article in English | MEDLINE | ID: mdl-37175976

ABSTRACT

The binding properties of synthetic and recombinant peptides derived from N-terminal part of ACE2, the main receptor for SARS-CoV-2, were evaluated. Additionally, the ability of these peptides to prevent virus entry in vitro was addressed using both pseudovirus particles decorated with the S protein, as well as through infection of Vero cells with live SARS-CoV-2 virus. Surprisingly, in spite of effective binding to S protein, all linear peptides of various lengths failed to neutralize the viral infection in vitro. However, the P1st peptide that was chemically "stapled" in order to stabilize its alpha-helical structure was able to interfere with virus entry into ACE2-expressing cells. Interestingly, this peptide also neutralized pseudovirus particles decorated with S protein derived from the Omicron BA.1 virus, in spite of variations in key amino acid residues contacting ACE2.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Chlorocebus aethiops , Humans , SARS-CoV-2/metabolism , Vero Cells , Angiotensin-Converting Enzyme 2/metabolism , Protein Binding , Peptides/pharmacology , Peptides/metabolism
7.
Int J Mol Sci ; 24(3)2023 Jan 19.
Article in English | MEDLINE | ID: mdl-36768315

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, is accompanied by a dysregulated immune response. In particular, NK cells, involved in the antiviral response, are affected by the infection. This study aimed to investigate circulating NK cells with a focus on their activation, depletion, changes in the surface expression of key receptors, and functional activity during COVID-19, among intensive care unit (ICU) patients, moderately ill patients, and convalescents (CCP). Our data confirmed that NK cell activation in patients with COVID-19 is accompanied by changes in circulating cytokines. The progression of COVID-19 was associated with a coordinated decrease in the proportion of NKG2D+ and CD16+ NK cells, and an increase in PD-1, which indicated their exhaustion. A higher content of NKG2D+ NK cells distinguished surviving patients from non-survivors in the ICU group. NK cell exhaustion in ICU patients was additionally confirmed by a strong negative correlation of PD-1 and natural cytotoxicity levels. In moderately ill patients and convalescents, correlations were found between the levels of CD57, NKG2C, and NKp30, which may indicate the formation of adaptive NK cells. A reduced NKp30 level was observed in patients with a lethal outcome. Altogether, the phenotypic changes in circulating NK cells of COVID-19 patients suggest that the intense activation of NK cells during SARS-CoV-2 infection, most likely induced by cytokines, is accompanied by NK cell exhaustion, the extent of which may be critical for the disease outcome.


Subject(s)
COVID-19 , Humans , Cytokines , SARS-CoV-2 , NK Cell Lectin-Like Receptor Subfamily K , Programmed Cell Death 1 Receptor , Killer Cells, Natural
8.
Int J Mol Sci ; 24(10)2023 May 20.
Article in English | MEDLINE | ID: mdl-37240393

ABSTRACT

The effectiveness of the antiviral immune response largely depends on the activation of cytotoxic T cells. The heterogeneous group of functionally active T cells expressing the CD56 molecule (NKT-like cells), that combines the properties of T lymphocytes and NK cells, is poorly studied in COVID-19. This work aimed to analyze the activation and differentiation of both circulating NKT-like cells and CD56- T cells during COVID-19 among intensive care unit (ICU) patients, moderate severity (MS) patients, and convalescents. A decreased proportion of CD56+ T cells was found in ICU patients with fatal outcome. Severe COVID-19 was accompanied by a decrease in the proportion of CD8+ T cells, mainly due to the CD56- cell death, and a redistribution of the NKT-like cell subset composition with a predominance of more differentiated cytotoxic CD8+ T cells. The differentiation process was accompanied by an increase in the proportions of KIR2DL2/3+ and NKp30+ cells in the CD56+ T cell subset of COVID-19 patients and convalescents. Decreased percentages of NKG2D+ and NKG2A+ cells and increased PD-1 and HLA-DR expression levels were found in both CD56- and CD56+ T cells, and can be considered as indicators of COVID-19 progression. In the CD56- T cell fraction, increased CD16 levels were observed in MS patients and in ICU patients with lethal outcome, suggesting a negative role for CD56-CD16+ T cells in COVID-19. Overall, our findings suggest an antiviral role of CD56+ T cells in COVID-19.


Subject(s)
CD8-Positive T-Lymphocytes , COVID-19 , Humans , COVID-19/metabolism , T-Lymphocyte Subsets , Killer Cells, Natural , Cell Differentiation
9.
Biochemistry (Mosc) ; 87(7): 590-604, 2022 Jul.
Article in English | MEDLINE | ID: mdl-36154880

ABSTRACT

Peptides are widely used for the diagnostics, prevention, and therapy of certain human diseases. How useful can they be for the disease caused by the SARS-CoV-2 coronavirus? In this review, we discuss the possibility of using synthetic and recombinant peptides and polypeptides for prevention of COVID-19 via blocking the interaction between the virus and its main receptor ACE2, as well as components of antiviral vaccines, in particular, against new emerging virus variants.


Subject(s)
COVID-19 , Angiotensin-Converting Enzyme 2 , Antiviral Agents/therapeutic use , Humans , Peptides/therapeutic use , SARS-CoV-2
10.
Int J Mol Sci ; 23(7)2022 Mar 24.
Article in English | MEDLINE | ID: mdl-35408882

ABSTRACT

Combined anti-cytokine therapy is a promising therapeutic approach for uncontrolled steroid-resistant asthma. In this regard, simultaneous blockade of IL-4 and IL-13 signaling by Dupilumab (anti-IL-4Ra monoclonal antibody) was recently approved for severe eosinophilic asthma. However, no therapeutic options for neutrophilic asthma are currently available. Recent advances in our understanding of asthma pathogenesis suggest that both IL-6 and TNF may represent potential targets for treatment of severe neutrophilic asthma. Nevertheless, the efficacy of simultaneous pharmacological inhibition of TNF and IL-6 in asthma was not yet studied. To evaluate the potency of combined cytokine inhibition, we simultaneously administrated IL-6 and TNF inhibitors to BALB/c mice with HDM-induced asthma. Combined IL-6/TNF inhibition, but not individual blockade of these two cytokines, led to complex anti-inflammatory effects including reduced Th2-induced eosinophilia and less prominent Th17/Th1-mediated neutrophilic infiltrate in the airways. Taken together, our results provide evidence for therapeutic potential of combined IL-6/TNF inhibition in severe steroid-resistant asthma.


Subject(s)
Asthma , Interleukin-6 , Animals , Cytokines , Disease Models, Animal , Interleukin-6/pharmacology , Mice , Mice, Inbred BALB C , Th1 Cells , Th17 Cells
11.
Proc Natl Acad Sci U S A ; 115(51): 13051-13056, 2018 12 18.
Article in English | MEDLINE | ID: mdl-30498033

ABSTRACT

TNF is a multifunctional cytokine involved in autoimmune disease pathogenesis that exerts its effects through two distinct TNF receptors, TNFR1 and TNFR2. While TNF- and TNFR1-deficient (but not TNFR2-deficient) mice show very similar phenotypes, the significance of TNFR2 signaling in health and disease remains incompletely understood. Recent studies implicated the importance of the TNF/TNFR2 axis in T regulatory (Treg) cell functions. To definitively ascertain the significance of TNFR2 signaling, we generated and validated doubly humanized TNF/TNFR2 mice, with the option of conditional inactivation of TNFR2. These mice carry a functional human TNF-TNFR2 (hTNF-hTNFR2) signaling module and provide a useful tool for comparative evaluation of TNF-directed biologics. Conditional inactivation of TNFR2 in FoxP3+ cells in doubly humanized TNF/TNFR2 mice down-regulated the expression of Treg signature molecules (such as FoxP3, CD25, CTLA-4, and GITR) and diminished Treg suppressive function in vitro. Consequently, Treg-restricted TNFR2 deficiency led to significant exacerbation of experimental autoimmune encephalomyelitis (EAE), accompanied by reduced capacity to control Th17-mediated immune responses. Our findings expose the intrinsic and beneficial effects of TNFR2 signaling in Treg cells that could translate into protective functions in vivo, including treatment of autoimmunity.


Subject(s)
Autoimmunity/immunology , Central Nervous System/immunology , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/prevention & control , Receptors, Tumor Necrosis Factor, Type II/physiology , T-Lymphocytes, Regulatory/immunology , Tumor Necrosis Factor-alpha/physiology , Animals , Cells, Cultured , Central Nervous System/metabolism , Central Nervous System/pathology , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/metabolism , Gene Expression Regulation , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout
12.
Ann Rheum Dis ; 79(11): 1453-1459, 2020 11.
Article in English | MEDLINE | ID: mdl-32796044

ABSTRACT

OBJECTIVES: Neutralisation of tumour necrosis factor (TNF) is widely used as a therapy for rheumatoid arthritis (RA). However, this therapy is only effective in less than a half of patients and is associated with several side effects. We hypothesised that TNF may possess non-redundant protective and immunomodulatory functions in vivo that cannot be blocked without a cost. The present work aimed to identify cellular sources of protective and pathogenic TNF, and its molecular forms during autoimmune arthritis. METHODS: Mice lacking TNF expression by distinct cell types, such as myeloid cells and T or B lymphocytes, were subjected to collagen-induced arthritis (CIA) and collagen antibody-induced arthritis. Mice lacking soluble TNF production were also employed. The severity and incidence of the disease, as well as humoral and cellular responses were assessed. RESULTS: Myeloid cell-derived TNF contributes to both induction and pathogenesis of autoimmune arthritis. Conversely, T cell-derived TNF is protective during the induction phase of arthritis via limiting of interleukin-12 production by dendritic cells and by subsequent control of autoreactive memory T cell development, but is dispensable during the effector phase of arthritis. B cell-derived TNF mediates severity of CIA via control of pathogenic autoantibody production. CONCLUSIONS: Distinct TNF-producing cell types may modulate disease development through different mechanisms, suggesting that in arthritis TNF ablation from restricted cellular sources, such as myeloid cells, while preserving protective TNF functions from other cell types may be superior to pan-anti-TNF therapy.


Subject(s)
Arthritis, Experimental/immunology , Myeloid Cells/immunology , Tumor Necrosis Factor-alpha/immunology , Animals , Arthritis, Experimental/metabolism , Arthritis, Experimental/pathology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Mice , Mice, Knockout , Myeloid Cells/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Tumor Necrosis Factor-alpha/metabolism
13.
Proc Natl Acad Sci U S A ; 113(11): 3006-11, 2016 Mar 15.
Article in English | MEDLINE | ID: mdl-26936954

ABSTRACT

Overexpression of TNF contributes to pathogenesis of multiple autoimmune diseases, accounting for a remarkable success of anti-TNF therapy. TNF is produced by a variety of cell types, and it can play either a beneficial or a deleterious role. In particular, in autoimmunity pathogenic TNF may be derived from restricted cellular sources. In this study we evaluated the feasibility of cell-type-restricted TNF inhibition in vivo. To this end, we engineered MYSTI (Myeloid-Specific TNF Inhibitor)--a recombinant bispecific antibody that binds to the F4/80 surface molecule on myeloid cells and to human TNF (hTNF). In macrophage cultures derived from TNF humanized mice MYSTI could capture the secreted hTNF, limiting its bioavailability. Additionally, as evaluated in TNF humanized mice, MYSTI was superior to an otherwise analogous systemic TNF inhibitor in protecting mice from lethal LPS/D-Galactosamine-induced hepatotoxicity. Our results suggest a novel and more specific approach to inhibiting TNF in pathologies primarily driven by macrophage-derived TNF.


Subject(s)
Antibodies, Bispecific/immunology , Antigens, Differentiation/immunology , Chemical and Drug Induced Liver Injury/therapy , Macrophages, Peritoneal/metabolism , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Amino Acid Substitution , Animals , Antibodies, Bispecific/genetics , Antibodies, Neutralizing/genetics , Antibodies, Neutralizing/immunology , Antibody Specificity , Antigen-Antibody Reactions , Antigens, Differentiation/genetics , Antigens, Surface/immunology , Camelus/immunology , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/immunology , Chemical and Drug Induced Liver Injury/prevention & control , Complementarity Determining Regions/chemistry , Complementarity Determining Regions/genetics , Complementarity Determining Regions/immunology , Galactosamine/toxicity , Genes, Synthetic , Humans , L Cells , Macrophages, Peritoneal/immunology , Mice , Mutation , Random Allocation , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/immunology , Single-Chain Antibodies/genetics , Single-Chain Antibodies/immunology , Tumor Necrosis Factor-alpha/metabolism
14.
Cytokine ; 101: 33-38, 2018 01.
Article in English | MEDLINE | ID: mdl-27624866

ABSTRACT

Cytokines are involved in a wide range of functions shaping the normal immune response, yet inflammatory changes in the immune system due to dysregulated cytokine signaling may lead to the induction of autoimmunity. Cytokine inhibitors have revolutionized the treatment of many autoimmune diseases in recent years. Systemic cytokine ablation, however, is often associated with the development of adverse side effects and some patients simply do not respond to therapy. TNF, IL-1 and IL-6 are the best characterized proinflammatory cytokines considered as the main therapeutic targets for the treatment of several autoimmune and inflammatory diseases. But can anti-cytokine therapy become more selective and thus more efficient? This mini-review discusses several recently emerging paradigms and summarizes current experimental attempts to validate them in mouse studies.


Subject(s)
Autoimmunity/immunology , Cytokines/antagonists & inhibitors , Disease Models, Animal , Immunotherapy , Animals , Autoimmune Diseases/immunology , Autoimmune Diseases/therapy , Cytokines/immunology , Inflammation/therapy , Interleukin-1/antagonists & inhibitors , Interleukin-6/antagonists & inhibitors , Mice , Tumor Necrosis Factor-alpha/antagonists & inhibitors
15.
Cytokine ; 89: 127-135, 2017 01.
Article in English | MEDLINE | ID: mdl-26854213

ABSTRACT

The link between inflammation and cancer was first proposed by R. Virchow. It was later realized that it is chronic inflammation that may promote cancer, whereas acute inflammation can actually block tumor development or even result in cure. Many molecular mediators of these diverse processes have been characterized only during the past 3 decades thanks to the advances in molecular and cellular techniques, as well as due to technologies of reverse genetics. In this chapter we discuss the role of Toll-like receptor (TLR) 4 signaling in cancer and contributions of proinflammatory cytokine signaling (whose expression may be driven by TLR-mediated signals) to tumor-promoting microenvironment. We also discuss recent clinical advances to target these pro-tumorigenic pathways at distinct stages of tumorigenesis.


Subject(s)
Cell Transformation, Neoplastic/immunology , Neoplasm Proteins/immunology , Neoplasms/immunology , Signal Transduction/immunology , Toll-Like Receptor 4/immunology , Tumor Microenvironment/immunology , Animals , Cell Transformation, Neoplastic/pathology , Cytokines/immunology , Humans , Neoplasms/pathology
16.
Infect Immun ; 83(9): 3612-23, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26123801

ABSTRACT

Tumor necrosis factor (TNF) is an important cytokine for host defense against pathogens but is also associated with the development of human immunopathologies. TNF blockade effectively ameliorates many chronic inflammatory conditions but compromises host immunity to tuberculosis. The search for novel, more specific human TNF blockers requires the development of a reliable animal model. We used a novel mouse model with complete replacement of the mouse TNF gene by its human ortholog (human TNF [huTNF] knock-in [KI] mice) to determine resistance to Mycobacterium bovis BCG and M. tuberculosis infections and to investigate whether TNF inhibitors in clinical use reduce host immunity. Our results show that macrophages from huTNF KI mice responded to BCG and lipopolysaccharide similarly to wild-type macrophages by NF-κB activation and cytokine production. While TNF-deficient mice rapidly succumbed to mycobacterial infection, huTNF KI mice survived, controlling the bacterial burden and activating bactericidal mechanisms. Administration of TNF-neutralizing biologics disrupted the control of mycobacterial infection in huTNF KI mice, leading to an increased bacterial burden and hyperinflammation. Thus, our findings demonstrate that human TNF can functionally replace murine TNF in vivo, providing mycobacterial resistance that could be compromised by TNF neutralization. This new animal model will be helpful for the testing of specific biologics neutralizing human TNF.


Subject(s)
Disease Models, Animal , Mycobacterium Infections/immunology , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology , Animals , Blotting, Western , Cytokines/biosynthesis , Flow Cytometry , Gene Knock-In Techniques/methods , Humans , Macrophages/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mycobacterium bovis/immunology , Mycobacterium tuberculosis/immunology
17.
Eur J Immunol ; 44(1): 251-64, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24009130

ABSTRACT

Tumor necrosis factor (TNF) is one of the key primary response genes in the immune system that can be activated by a variety of stimuli. Previous analysis of chromatin accessibility to DNaseI demonstrated open chromatin conformation of the TNF proximal promoter in T cells. Here, using chromatin probing with restriction enzyme EcoNI and micrococcal nuclease we show that in contrast to the proximal promoter, the TNF transcription start site remains in a closed chromatin configuration in primary T helper (Th) cells, but acquires an open state after activation or polarization under Th1 and Th17 conditions. We further demonstrate that transcription factor c-Jun plays a pivotal role in the maintenance of open chromatin conformation at the transcription start site of the TNF gene.


Subject(s)
Chromatin/metabolism , Proto-Oncogene Proteins c-jun/metabolism , T-Lymphocyte Subsets/immunology , Th1 Cells/immunology , Th17 Cells/immunology , Tumor Necrosis Factor-alpha/metabolism , Animals , Cell Line , Cellular Microenvironment , Mice , Mice, Inbred C57BL , Micrococcal Nuclease/metabolism , Promoter Regions, Genetic/genetics , Protein Conformation , Proto-Oncogene Proteins c-jun/genetics , Transcription Initiation Site , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology
18.
J Leukoc Biol ; 2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38941443

ABSTRACT

Itaconate is one of the most studied immunometabolites produced by myeloid cells during inflammatory response. It mediates a wide range of anti-inflammatory and immunoregulatory effects and plays a role in a number of pathological states, including autoimmunity and cancer. Itaconate and its derivatives are considered as potential therapeutic agents for treatment of inflammatory diseases. While immunoregulatory effects of itaconate have been extensively studied in vitro and using knock-out mouse models, less is known about how therapeutic administration of this metabolite regulates inflammatory response in vivo. Here, we investigate the immunoregulatory properties of exogenous administration of itaconate (ITA) and its derivative dimethyl itaconate (DI) in a mouse model of LPS-induced inflammation. The data show that administration of ITA or DI controls systemic production of multiple cytokines, including increased IL-10 production. However, only DI was able to suppress systemic production of IFNγ and IL-1ß. In contrast to in vitro data, administration of ITA or DI in vivo resulted in systemic upregulation of IL-6 in the blood. Electrophilic stress due to ITA or DI was not responsible for IL-6 upregulation. However, inhibition of SDH with dimethyl malonate (DM) also resulted in elevated systemic levels of IL-6 and IL-10. Taken together, our study reports a novel effect of exogenous itaconate and its derivative DI on the production of IL-6 in vivo, with important implications for the development of itaconate-based anti-inflammatory therapies.

19.
Front Immunol ; 14: 1172467, 2023.
Article in English | MEDLINE | ID: mdl-37153552

ABSTRACT

The naked mole-rat (NMR) is a unique long-lived rodent which is highly resistant to age-associated disorders and cancer. The immune system of NMR possesses a distinct cellular composition with the prevalence of myeloid cells. Thus, the detailed phenotypical and functional assessment of NMR myeloid cell compartment may uncover novel mechanisms of immunoregulation and healthy aging. In this study gene expression signatures, reactive nitrogen species and cytokine production, as well as metabolic activity of classically (M1) and alternatively (M2) activated NMR bone marrow-derived macrophages (BMDM) were examined. Polarization of NMR macrophages under pro-inflammatory conditions led to expected M1 phenotype characterized by increased pro-inflammatory gene expression, cytokine production and aerobic glycolysis, but paralleled by reduced production of nitric oxide (NO). Under systemic LPS-induced inflammatory conditions NO production also was not detected in NMR blood monocytes. Altogether, our results indicate that NMR macrophages are capable of transcriptional and metabolic reprogramming under polarizing stimuli, however, NMR M1 possesses species-specific signatures as compared to murine M1, implicating distinct adaptations in NMR immune system.


Subject(s)
Cytokines , Macrophages , Mice , Animals , Phenotype , Cytokines/metabolism , Mole Rats
20.
Vaccines (Basel) ; 11(6)2023 May 31.
Article in English | MEDLINE | ID: mdl-37376436

ABSTRACT

A highly effective humoral immune response induced by the Sputnik V vaccine was demonstrated in independent studies, as well as in large-scale post-vaccination follow-up studies. However, the shifts in the cell-mediated immunity induced by Sputnik V vaccination are still under investigation. This study was aimed at estimating the impact of Sputnik V on activating and inhibitory receptors, activation and proliferative senescence markers in NK and T lymphocytes. The effects of Sputnik V were evaluated by the comparison of PBMC samples prior to vaccination, and then three days and three weeks following the second (boost) dose. The prime-boost format of Sputnik V vaccination induced a contraction in the T cell fraction of senescent CD57+ cells and a decrease in HLA-DR-expressing T cells. The proportion of NKG2A+ T cells was down-regulated after vaccination, whereas the PD-1 level was not affected significantly. A temporal increase in activation levels of NK cells and NKT-like cells was recorded, dependent on whether the individuals had COVID-19 prior to vaccination. A short-term elevation of the activating NKG2D and CD16 was observed in NK cells. Overall, the findings of the study are in favor of the Sputnik V vaccine not provoking a dramatic phenotypic rearrangement in T and NK cells, although it induces their slight temporal non-specific activation.

SELECTION OF CITATIONS
SEARCH DETAIL