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Andrey Kruglov

Leibniz Association

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Sergei A. Nedospasov

Lomonosov Moscow State University

Marina S. Drutskaya

Sirius University of Science and Technology

Dmitry V. Kuprash

Engelhardt Institute of Molecular Biology

Mir‐Farzin Mashreghi

German Rheumatism Research Centre

Grigory A. Efimov

National Research Center for Hematology Russian Academy of Medical Sciences

Alexei V. Tumanov

The University of Texas Health Science Center at San Antonio

Marina Bondareva

German Rheumatism Research Centre

Pawel Durek

German Rheumatism Research Centre

Frederik Heinrich

German Rheumatism Research Centre

Andreas Radbruch

German Rheumatism Research Centre

Cooperative Institutions

Charité - Universitätsmedizin Berlin

Humboldt-Universität zu Berlin

German Rheumatism Research Centre

Freie Universität Berlin

Leibniz Association

Institute of Immunology

Engelhardt Institute of Molecular Biology

Russian Academy of Sciences

Lomonosov Moscow State University

Universität Hamburg

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Accelerated thymic atrophy as a result of elevated homeostatic expression of the genes encoded by the TNF/lymphotoxin cytokine locus

European Journal of Immunology (2009)

Dmitry J. Liepinsh Andrey Kruglov A R Galimov Alexander N. Shakhov Yuriy V. Shebzukhov

TNF, lymphotoxin (LT)-alpha, LT-beta and LIGHT are members of a larger superfamily of TNF-related cytokines that can cross-utilize several receptors. Although LIGHT has been implicated in thymic development and function, the role of TNF and LT remains incompletely defined. To address this, we created a model of modest homeostatic overexpression of TNF/LT cytokines using the genomic human TNF/LT locus as a low copy number Tg. Strikingly, expression of Tg TNF/LT gene products led to profound early thymic atrophy characterized by decreased numbers of thymocytes and cortical thymic epithelial cells, partial block of thymocyte proliferation at double negative (DN) 1 stage, increased apoptosis of DN2 thymocytes and severe decline of T-cell numbers in the periphery. Results of backcrossing to TNFR1-, LTbetaR- or TNF/LT-deficient backgrounds and of reciprocal bone marrow transfers implicated both LT-alpha/LT-beta to LTbetaR and TNF/LT-alpha to TNFR1 signaling in accelerated thymus degeneration. We hypothesize that chronic infections can promote thymic atrophy by upregulating LT and TNF production.

Lymphotoxin alpha

Thymocyte

Cytokine receptor

Thymic involution

Lymphotoxin beta receptor

Homeostasis

10.1002/eji.200839191

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Citations (33)

Comment on “Experimental Arthritis Triggers Periodontal Disease in Mice: Involvement of TNF-α and the Oral Microbiota”

The Journal of Immunology (2011)

Andrey Kruglov Sergei A. Nedospasov

We have read with interest the article by Queiroz-Junior et al. ([1][1]) in which TNF was found to mediate periodontal disease during experimental arthritis in mice. The evidence is based on the therapeutic effects of infliximab, a chimeric mAb used in clinic to neutralize human TNF. Although we are

10.4049/jimmunol.1190080

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Citations (27)

Making anti-cytokine therapy more selective: Studies in mice

Cytokine (2016)

Marina S. Drutskaya Grigory A. Efimov Irina V. Astrakhantseva Andrey Kruglov Sergei A. Nedospasov

Proinflammatory cytokine

10.1016/j.cyto.2016.08.022

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Citations (15)

IL22BP Mediates the Antitumor Effects of Lymphotoxin Against Colorectal Tumors in Mice and Humans

Gastroenterology (2020)

Jan Kempski Anastasios D. Giannou Kristoffer Riecken Lilan Zhao Babett Steglich

Background & AimsUnregulated activity of interleukin (IL) 22 promotes intestinal tumorigenesis in mice. IL22 binds the antagonist IL22 subunit alpha 2 (IL22RA2, also called IL22BP). We studied whether alterations in IL22BP contribute to colorectal carcinogenesis in humans and mice.MethodsWe obtained tumor and nontumor tissues from patients with colorectal cancer (CRC) and measured levels of cytokines by quantitative polymerase chain reaction, flow cytometry, and immunohistochemistry. We measured levels of Il22bp messenger RNA in colon tissues from wild-type, Tnf–/–, Lta–/–, and Ltb–/– mice. Mice were given azoxymethane and dextran sodium sulfate to induce colitis and associated cancer or intracecal injections of MC38 tumor cells. Some mice were given inhibitors of lymphotoxin beta receptor (LTBR). Intestine tissues were analyzed by single-cell sequencing to identify cell sources of lymphotoxin. We performed immunohistochemistry analysis of colon tissue microarrays from patients with CRC (1475 tissue cores, contained tumor and nontumor tissues) and correlated levels of IL22BP with patient survival times.ResultsLevels of IL22BP were decreased in human colorectal tumors, compared with nontumor tissues, and correlated with levels of lymphotoxin. LTBR signaling was required for expression of IL22BP in colon tissues of mice. Wild-type mice given LTBR inhibitors had an increased tumor burden in both models, but LTBR inhibitors did not increase tumor growth in Il22bp–/– mice. Lymphotoxin directly induced expression of IL22BP in cultured human monocyte–derived dendritic cells via activation of nuclear factor κB. Reduced levels of IL22BP in colorectal tumor tissues were associated with shorter survival times of patients with CRC.ConclusionsLymphotoxin signaling regulates expression of IL22BP in colon; levels of IL22BP are reduced in human colorectal tumors, associated with shorter survival times. LTBR signaling regulates expression of IL22BP in colon tumors in mice and cultured human dendritic cells. Patients with colorectal tumors that express low levels of IL22BP might benefit from treatment with an IL22 antagonist. Unregulated activity of interleukin (IL) 22 promotes intestinal tumorigenesis in mice. IL22 binds the antagonist IL22 subunit alpha 2 (IL22RA2, also called IL22BP). We studied whether alterations in IL22BP contribute to colorectal carcinogenesis in humans and mice. We obtained tumor and nontumor tissues from patients with colorectal cancer (CRC) and measured levels of cytokines by quantitative polymerase chain reaction, flow cytometry, and immunohistochemistry. We measured levels of Il22bp messenger RNA in colon tissues from wild-type, Tnf–/–, Lta–/–, and Ltb–/– mice. Mice were given azoxymethane and dextran sodium sulfate to induce colitis and associated cancer or intracecal injections of MC38 tumor cells. Some mice were given inhibitors of lymphotoxin beta receptor (LTBR). Intestine tissues were analyzed by single-cell sequencing to identify cell sources of lymphotoxin. We performed immunohistochemistry analysis of colon tissue microarrays from patients with CRC (1475 tissue cores, contained tumor and nontumor tissues) and correlated levels of IL22BP with patient survival times. Levels of IL22BP were decreased in human colorectal tumors, compared with nontumor tissues, and correlated with levels of lymphotoxin. LTBR signaling was required for expression of IL22BP in colon tissues of mice. Wild-type mice given LTBR inhibitors had an increased tumor burden in both models, but LTBR inhibitors did not increase tumor growth in Il22bp–/– mice. Lymphotoxin directly induced expression of IL22BP in cultured human monocyte–derived dendritic cells via activation of nuclear factor κB. Reduced levels of IL22BP in colorectal tumor tissues were associated with shorter survival times of patients with CRC. Lymphotoxin signaling regulates expression of IL22BP in colon; levels of IL22BP are reduced in human colorectal tumors, associated with shorter survival times. LTBR signaling regulates expression of IL22BP in colon tumors in mice and cultured human dendritic cells. Patients with colorectal tumors that express low levels of IL22BP might benefit from treatment with an IL22 antagonist.

Lymphotoxin beta receptor

10.1053/j.gastro.2020.06.033

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Citations (38)

Cellular source and molecular form of TNF specify its distinct functions in organization of secondary lymphoid organs

Alexei V. Tumanov Sergei I. Grivennikov Andrey Kruglov Yuriy V. Shebzukhov Ekaterina P. Koroleva

Follicular dendritic cells

10.1182/blood-2009-10-249177

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Citations (92)

Synchronization of Wave Flows of Arterial and Venous Blood with Phases of the Cardiac Cycle in Norm: Part 5

International Journal of Biomedicine (2022)

Alexander G Kruglov Valery N Utkin Alexander Yu Vasilyev Andrey Kruglov

The muscular-fibrous frame of the heart (MFFH) synchronizes and compensates for the pressor effect of the myocardium between the high/low-energy regions (left/right) of the heart. The anatomical structures of MFFH (plastic muscular-fibrous formation with a phase change in contours, valves, valve rings) form the "cardiac mean integral pressure" (CMIP). MFFH, a variable spatial structure, forms the starting pressor levels of “opening/closing” of valves and hemodynamic vectors of the heart chambers, systemic and pulmonary circulation, and also compensates for excess pressor pressure (having a variable gradient) at the boundaries of the heart chambers. Throughout the cardiac cycle (CC), on the path "venous block-lung-arterial block-aorta," variable pressure values, compensated by the structures of MFFH, are formed between the blood flows of the right and left parts of the heart. A mutual adaptation of SVs of the ventricles is formed by phase-by-phase compensatory plastics of MFFH. CMIP of MFFH is an integral indicator, where each point reflects: 1) CC phase (time and place); 2) the average value of the range of values in which the equilibrium point of pressor compensation between the high/low-energy processes of this CC phase is located. CMIP is a vector of the MFFH phase dynamics, which compensates for the excess pressor effect with a changing gradient through CC.

Cardiac cycle

Pressure gradient

10.21103/article12(2)_oa4

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Citations (6)

Tumor necrosis factor, lymphotoxin and cancer

IUBMB Life (2010)

Marina S. Drutskaya Grigory A. Efimov Andrey Kruglov Dmitry V. Kuprash Sergei A. Nedospasov

Initially TNF has been discovered as an anti-tumor factor, but it is now considered as one of the universal effectors of innate signaling implicating its key role in host defense and inflammation. Other physiological functions of TNF are primarily linked to organization of lymphoid tissues. TNF can exert deleterious effects on the organism when its local or systemic concentrations exceed certain levels. This is the main reason for the failure of TNF therapy in oncology. Moreover, in certain experimental models TNF to TNFRp55 signaling axis was found to play a pro-tumorigenic role. On the other hand, anti-TNF therapy proved to be beneficial in rheumatic and other autoimmune diseases. Taking into consideration the pivotal function of TNF in the immune system, it is obvious that such therapy cannot be entirely free of adverse effects including suppression of host defense and, possibly, predisposition to lymphomas. Lymphotoxins alpha and beta are the two related cytokines that exist in distinct trimeric forms which can signal through TNFR I and TNFR II, as well LTbetaR receptors, depending on the composition of the trimer. These signals have important functions in the development and homeostasis of the immune system. Importantly, there is a recently uncovered link between the LTalpha/LTbeta to LTbetaR signaling axis and cancer. Here we review the current status of the field with the focus on one particular issue: are TNF and lymphotoxins intrinsically anti-cancer or pro-tumorigenic.

Lymphotoxin beta receptor

Lymphotoxin alpha

10.1002/iub.309

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Citations (32)

P038 In vivo demonstration of tmTNF reverse signaling: significance in the therapeutic response to anti-TNF agents during murine arthritis

Annals of the Rheumatic Diseases (2019)

Benjamin Rauwel Numa Simons Katy Diallo Michel Baron Yannick Degboé

Career situation of first and presenting author

Post-doctoral fellow.

Introduction

Anti-TNF agents are widely used in rheumatoid arthritis (RA). Their effect on inflammation results from the neutralization of soluble TNF (sTNF), but also supposedly from the induction of reverse signaling through their binding to membrane TNF (tmTNF). Despite possible clinical relevance, reverse signaling has been described only in vitro but has not been proven in vivo.

Objectives

In this study we aim to demonstrate for the first time the existence of tmTNF reverse signaling in vivo and its importance in anti-TNF response during arthritis.

Methods

Triple transgenic mouse model (3TG), KO for TNFR1/TNFR2 and KI for tmTNF, thus secreting no sTNF was developed. To analyze reverse signaling, mice were injected either with etanercept (ETA, 10 mg/kg), an anti-mouse TNF antibody (MP6-XT22, rat IgG1, 10 mg/kg) or an anti-human IL17 antibody (secukinumab, SEC, 10 mg/kg) as a control. Daily clinical evaluation of K/BxN serum induced-arthritis was performed in 3TG as well as WT mice. Polarization of bone marrow-derived macrophages (BMDM) and cytokine production from non-arthritic WT and 3TG mice under the action of anti-TNF in vitro was evaluated by RT-qPCR, CBA and ELISA.

Results

In vivo, the administration of anti-TNF (ETA or MP6-XT22) decreased arthritic scores in WT mice (p=0.005) as well as in 3TG mice (p<0.001), unlike SEC which had no effect, proving that anti-TNF binding of tmTNF decreased arthritis. In vitro effect of anti-TNF on BMDM from WT as well as 3TG mice induced a decrease in the expression of genes specific of inflammatory macrophages (CD38, GpR18 and FpR2), and an increase in the expression of genes specific of alternative macrophages (Arg1, EgR2, c-Myc). We also observed an inhibition of the secretion of pro-inflammatory cytokines (IL12p70 and IL-6) and an early peak of IL-10 secretion demonstrating an effect of reverse signaling on macrophage polarization and activation. This suggested a switch in macrophage polarization as a probable mechanism for modulation of inflammation during K/BxN serum-induced arthritis.

Conclusions

Our work provides in vivo evidence for the involvement of reverse signaling in the anti-TNF-mediated modulation of arthritis. Reverse signaling is expected to result in the modulation of macrophage polarization from an inflammatory to an alternative functional phenotype in arthritic mice. Our data prompt us to consider new interpretation of the effects of anti-TNF in the treatment of RA.

Disclosure of Interest

None declared.

10.1136/annrheumdis-2018-ewrr2019.30

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Specific microbiota enhances intestinal IgA levels by inducing TGF‐β in T follicular helper cells of Peyer's patches in mice

European Journal of Immunology (2020)

Alexander Beller Andrey Kruglov Pawel Durek Victoria von Goetze Katharina Werner

Abstract In humans and mice, mucosal immune responses are dominated by IgA antibodies and the cytokine TGF‐β, suppressing unwanted immune reactions but also targeting Ig class switching to IgA. It had been suggested that eosinophils promote the generation and maintenance of mucosal IgA‐expressing plasma cells. Here, we demonstrate that not eosinophils, but specific bacteria determine mucosal IgA production. Co‐housing of eosinophil‐deficient mice with mice having high intestinal IgA levels, as well as the intentional microbiota transfer induces TGF‐β expression in intestinal T follicular helper cells, thereby promoting IgA class switching in Peyer's patches, enhancing IgA + plasma cell numbers in the small intestinal lamina propria and levels of mucosal IgA. We show that bacteria highly enriched for the genus Anaeroplasma are sufficient to induce these changes and enhance IgA levels when adoptively transferred. Thus, specific members of the intestinal microbiota and not the microbiota as such regulate gut homeostasis, by promoting the expression of immune‐regulatory TGF‐β and of mucosal IgA.

Immunoglobulin A

Peyer's patch

Lamina propria

10.1002/eji.201948474

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Citations (62)

Cytokines, reverse genetics and anti-cytokine therapy

Bulletin of Siberian Medicine (2019)

Marina S. Drutskaya Ekaterina O. Gubernatorova Ekaterina N. Gorshkova K.-S. N. Athertkhany М. А. Носенко

Cytokines comprise the molecular language of communication between the cells, which is needed to maintain the homeostatic functions of the body (including the immune system) and mediate various diseases. Many aspects of inflammation, autoimmune diseases and neoplasia are associated with cytokine signaling through specific receptors. The establishment of new physiological functions of “old” cytokines and understanding the molecular and cellular mechanisms of their involvement in disease pathogenesis, as well as the search for new therapeutic targets and development of innovative approaches to anti-cytokine therapy, present a fundamental problem. When assessing the tremendous success of anti-cytokine therapy in treatment of certain autoimmune diseases, we should not forget that (a) this treatment does not eliminate the causes of the disease:autoreactive T-cell clones; and that (b) less than half of the patients respond to this therapy; and that (c) anti-cytokine therapy has serious side effects.

Pathogenesis

10.20538/1682-0363-2019-1-38-48

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