المؤلفون: Buys, Willem, Bick, Alexandra, Madel, Rabea J., Westendorf, Astrid M., Buer, Jan, Herbstreit, Frank, Kirschning, Carsten J., Peters, Jürgen

مصطلحات موضوعية: ScholarlyArticle, ddc:610, Medizinische Fakultät » Universitätsklinikum Essen » Klinik für Anästhesiologie und Intensivmedizin, Medizinische Fakultät » Universitätsklinikum Essen » Institut für Medizinische Mikrobiologie, whole blood assay -- cytokine -- early sepsis -- hyperinflammation -- immune modulation -- toll-like receptor -- heterogeneity

الوصف: Introduction: Early sepsis is a life-threatening immune dysregulation believed to feature a “cytokine storm” due to activation of pattern recognition receptors by pathogen and danger associated molecular patterns. However, treatments with single toll-like receptor (TLR) blockers have shown no clinical benefit. We speculated that sepsis patients at the time of diagnosis are heterogeneous in relation to their cytokine production and its potential inhibition by a triple cocktail of TLR blockers. Accordingly, we analyzed inflammatory cytokine production in whole blood assays from early sepsis patients and determined the effects of triple TLR-blockade. Methods: Whole blood of 51 intensive care patients sampled within 24h of meeting Sepsis-3 criteria was incubated for 6h without or with specific TLR2, 4, and 7/8 stimuli or suspensions of heat-killed S. aureus or E. coli bacteria as pan-TLR challenges, and also with a combination of monoclonal antibodies against TLR2 and 4 and chloroquine (endosomal TLR inhibition), subsequent to dose optimization. Concentrations of tumor necrosis factor (TNF), Interleukin(IL)-6, IL-8, IL-10, IL-1α and IL-1β were measured (multiplex ELISA) before and after incubation. Samples from 11 sex and age-matched healthy volunteers served as controls and for dose-finding studies. Results: Only a fraction of sepsis patient samples revealed ongoing cytokine production ex vivo despite sampling within 24 h of first meeting Sepsis-3 criteria. In dose finding studies, inhibition of TLR2, 4 and endosomal TLRs reliably suppressed cytokine production to specific TLR agonists and added bacteria. However, inflammatory cytokine production ex vivo was only suppressed in the high cytokine producing samples but not in the majority. The suppressive response to TLR-blockade correlated both with intraassay inflammatory cytokine production (r=0.29–0.68; p<0.0001–0.04) and cytokine baseline concentrations (r=0.55; p<0.0001). Discussion: Upon meeting Sepsis-3 criteria for less than 24 h, a mere quarter of ...

العلاقة: https://doi.org/10.3389/fimmu.2023.1277033Test; https://nbn-resolving.org/urn:nbn:de:hbz:465-20240415-165121-0Test; https://duepublico2.uni-due.de/receive/duepublico_mods_00079159Test; https://duepublico2.uni-due.de/servlets/MCRFileNodeServlet/duepublico_derivate_00081353/fimmu_2023_14-1277033.pdfTest

الإتاحة: https://doi.org/10.3389/fimmu.2023.1277033Test
https://nbn-resolving.org/urn:nbn:de:hbz:465-20240415-165121-0Test
https://duepublico2.uni-due.de/receive/duepublico_mods_00079159Test
https://duepublico2.uni-due.de/servlets/MCRFileNodeServlet/duepublico_derivate_00081353/fimmu_2023_14-1277033.pdfTest

المؤلفون: Wyczanska, Maja, Rohling, Jana, Keller, Ursula, Benz, Marcus R., Kirschning, Carsten, Lange-Sperandio, Bärbel

المساهمون: Theilig, Franziska, Deutsche Forschungsgemeinschaft

المصدر: PLOS ONE ; volume 18, issue 11, page e0294142 ; ISSN 1932-6203

الوصف: Urinary tract obstruction during renal development leads to inflammation, tubular apoptosis, and interstitial fibrosis. Toll like receptors (TLRs) expressed on leukocytes, myofibroblasts and renal cells play a central role in acute inflammation. TLR2 is activated by endogenous danger signals in the kidney; its contribution to renal injury in early life is still a controversial topic. We analyzed TLR2 for a potential role in the neonatal mouse model of congenital obstructive nephropathy. Inborn obstructive nephropathies are a leading cause of end-stage kidney disease in children. Thus, newborn Tlr2 -/- and wild type (WT) C57BL/6 mice were subjected to complete unilateral ureteral obstruction (UUO) or sham-operation on the 2 nd day of life. The neonatal kidneys were harvested and analyzed at days 7 and 14 of life. Relative expression levels of TLR2, caspase-8, Bcl-2, Bax, GSDMD, GSDME, HMGB1, TNF, galectin-3, α-SMA, MMP-2, and TGF-β proteins were quantified semi-quantitatively by immunoblot analyses. Tubular apoptosis, proliferation, macrophage- and T-cell infiltration, tubular atrophy, and interstitial fibrosis were analyzed immunohistochemically. Neonatal Tlr2 -/- mice kidneys exhibited less tubular and interstitial apoptosis as compared to those of WT C57BL/6 mice after UUO. UUO induced neonatally did trigger pyroptosis in kidneys, however to similar degrees in Tlr2 -/- and WT mice. Also, tubular atrophy, interstitial fibrosis, tubular proliferation, as well as macrophage and T-cell infiltration were unremarkable. We conclude that while TLR2 mediates apoptosis in the kidneys of neonatal mice subjected to UUO, leukocyte recruitment, interstitial fibrosis, and consequent neonatal obstructive nephropathy might lack a TLR2 involvement.

الإتاحة: https://doi.org/10.1371/journal.pone.0294142Test

المؤلفون: Madel, Rabea J., Börger, Verena, Dittrich, Robin, Bremer, Michel, Tertel, Tobias, Phuong, Nhi Ngo Thi, Baba, Hideo A., Kordelas, Lambros, Staubach, Simon, Stein, Frank, Haberkant, Per, Hackl, Matthias, Grillari, Regina, Grillari, Johannes, Buer, Jan, Horn, Peter A., Westendorf, Astrid M., Brandau, Sven, Kirschning, Carsten J., Giebel, Bernd

المصدر: Cytotherapy ; volume 25, issue 8, page 821-836 ; ISSN 1465-3249

مصطلحات موضوعية: Cancer Research, Transplantation, Cell Biology, Genetics (clinical), Oncology, Immunology, Immunology and Allergy

الإتاحة: https://doi.org/10.1016/j.jcyt.2023.03.008Test
https://api.elsevier.com/content/article/PII:S1465324923000701?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S1465324923000701?httpAccept=text/plainTest

المؤلفون: Bick, Alexandra, Buys, Willem, Engler, Andrea, Madel, Rabea, Atia, Mazen, Faro, Francesca, Westendorf, Astrid M., Limmer, Andreas, Buer, Jan, Herbstreit, Frank, Kirschning, Carsten J., Peters, Jürgen

مصطلحات موضوعية: ddc:610, Medizinische Fakultät » Universitätsklinikum Essen » Klinik für Anästhesiologie und Intensivmedizin, Medizinische Fakultät » Universitätsklinikum Essen » Institut für Medizinische Mikrobiologie

الوصف: Rationale: The immune profile of sepsis patients is incompletely understood and hyperinflammation and hypoinflammation may occur concurrently or sequentially. Immune checkpoint inhibition (ICI) may counter hypoinflammation but effects are uncertain. We tested the reactivity of septic whole blood to bacteria, Toll-like receptor (TLR) ligands and to ICI. Methods: Whole blood assays of 61 patients' samples within 24h of meeting sepsis-3 criteria and 12 age and sex-matched healthy volunteers. Measurements included pattern/danger-associated molecular pattern (P/DAMP), cytokine concentrations at baseline and in response to TLR 2, 4, and 7/8 ligands, heat-inactivated Staphylococcus aureus or Escherichia coli, E.coli lipopolysaccharide (LPS), concentration of soluble and cellular immune checkpoint molecules, and cytokine concentrations in response to ICI directed against programmed-death receptor 1 (PD1), PD1-ligand 1, or cytotoxic T-lymphocyte antigen 4, both in the absence and presence of LPS. Main results: In sepsis, concentrations of P/DAMPs and inflammatory cytokines were increased and the latter increased further upon incubation ex vivo. However, cytokine responses to TLR 2, 4, and 7/8 ligands, heat-inactivated S. aureus or E. coli, and E. coli LPS were all depressed. Depression of the response to LPS was associated with increased in-hospital mortality. Despite increased PD-1 expression on monocytes and T-cells, and monocyte CTLA-4 expression, however, addition of corresponding checkpoint inhibitors to assays failed to increase inflammatory cytokine concentrations in the absence and presence of LPS. Conclusion: Patients first meeting Sepsis-3 criteria reveal 1) depressed responses to multiple TLR-ligands, bacteria, and bacterial LPS, despite concomitant inflammation, but 2) no response to immune checkpoint inhibition.

العلاقة: https://doi.org/10.1371/journal.pone.0273247Test; https://nbn-resolving.org/urn:nbn:de:hbz:465-20220920-150605-5Test; https://duepublico2.uni-due.de/receive/duepublico_mods_00076911Test; https://duepublico2.uni-due.de/servlets/MCRFileNodeServlet/duepublico_derivate_00076639/pone_2022_0273247.pdfTest

الإتاحة: https://doi.org/10.1371/journal.pone.0273247Test
https://nbn-resolving.org/urn:nbn:de:hbz:465-20220920-150605-5Test
https://duepublico2.uni-due.de/receive/duepublico_mods_00076911Test
https://duepublico2.uni-due.de/servlets/MCRFileNodeServlet/duepublico_derivate_00076639/pone_2022_0273247.pdfTest

المؤلفون: Teske, Nina C., Engelen-Lee, Joo-Yeon, Dyckhoff-Shen, Susanne, Pfister, Hans-Walter, Klein, Matthias, van de Beek, Diederik, Kirschning, Carsten K., Koedel, Uwe, Brouwer, Matthijs C.

المساهمون: European Society of Clinical Microbiology and Infectious Diseases, European Federation of Neurological Sciences, Netherlands Organization for Health Research and Development

المصدر: Acta Neuropathologica Communications ; volume 10, issue 1 ; ISSN 2051-5960

مصطلحات موضوعية: Cellular and Molecular Neuroscience, Neurology (clinical), Pathology and Forensic Medicine

الوصف: Pneumococcal meningitis is associated with dysregulation of the coagulation cascade. Previously, we detected upregulation of cerebral plasminogen activator inhibitor-2 (PAI-2) mRNA expression during pneumococcal meningitis. Diverse functions have been ascribed to PAI-2, but its role remains unclear. We analyzed the function of SERPINB2 (coding for PAI-2) in patients with bacterial meningitis, in a well-established pneumococcal meningitis mouse model, using Serpinb2 knockout mice, and in vitro in wt and PAI-2-deficient bone marrow-derived macrophages (BMDMs). We measured PAI-2 in cerebrospinal fluid of patients, and performed functional, histopathological, protein and mRNA expression analyses in vivo and in vitro. We found a substantial increase of PAI-2 concentration in CSF of patients with pneumococcal meningitis, and up-regulation and increased release of PAI-2 in mice. PAI-2 deficiency was associated with increased mortality in murine pneumococcal meningitis and cerebral hemorrhages. Serpinb2 −/ − mice exhibited increased C5a levels, but decreased IL-10 levels in the brain during pneumococcal infection. Our in vitro experiments confirmed increased expression and release of PAI-2 by wt BMDM and decreased IL-10 liberation by PAI-2-deficient BMDM upon pneumococcal challenge. Our data show that PAI-2 is elevated during in pneumococcal meningitis in humans and mice. PAI-2 deficiency causes an inflammatory imbalance, resulting in increased brain pathology and mortality.

الإتاحة: https://doi.org/10.1186/s40478-022-01461-1Test

المؤلفون: Yang, Xiaoli, Ali, Shafaqat, Zhao, Manman, Richter, Lisa, Schäfer, Vanessa, Schliehe-Diecks, Julian, Frank, Marian, Qi, Jing, Larsen, Pia-Katharina, Skerra, Jennifer, Islam, Heba, Wachtmeister, Thorsten, Alter, Christina, Huang, Anfei, Bhatia, Sanil, Köhrer, Karl, Kirschning, Carsten, Weighardt, Heike, Kalinke, Ulrich, Kalscheuer, Rainer, Uhrberg, Markus, Scheu, Stefanie

المساهمون: Deutsche Forschungsgemeinschaft

المصدر: Frontiers in Immunology ; volume 13 ; ISSN 1664-3224

مصطلحات موضوعية: Immunology, Immunology and Allergy

الوصف: Beauvericin (BEA), a mycotoxin of the enniatin family produced by various toxigenic fungi, has been attributed multiple biological activities such as anti-cancer, anti-inflammatory, and anti-microbial functions. However, effects of BEA on dendritic cells remain unknown so far. Here, we identified effects of BEA on murine granulocyte–macrophage colony-stimulating factor (GM-CSF)-cultured bone marrow derived dendritic cells (BMDCs) and the underlying molecular mechanisms. BEA potently activates BMDCs as signified by elevated IL-12 and CD86 expression. Multiplex immunoassays performed on myeloid differentiation primary response 88 (MyD88) and toll/interleukin-1 receptor (TIR) domain containing adaptor inducing interferon beta (TRIF) single or double deficient BMDCs indicate that BEA induces inflammatory cytokine and chemokine production in a MyD88/TRIF dependent manner. Furthermore, we found that BEA was not able to induce IL-12 or IFNβ production in Toll-like receptor 4 ( Tlr4 )-deficient BMDCs, whereas induction of these cytokines was not compromised in Tlr3/7/9 deficient BMDCs. This suggests that TLR4 might be the functional target of BEA on BMDCs. Consistently, in luciferase reporter assays BEA stimulation significantly promotes NF-κB activation in mTLR4/CD14/MD2 overexpressing but not control HEK-293 cells. RNA-sequencing analyses further confirmed that BEA induces transcriptional changes associated with the TLR4 signaling pathway. Together, these results identify TLR4 as a cellular BEA sensor and define BEA as a potent activator of BMDCs, implying that this compound can be exploited as a promising candidate structure for vaccine adjuvants or cancer immunotherapies.

الإتاحة: https://doi.org/10.3389/fimmu.2022.856230Test

المؤلفون: Meng, Guangxun, Kirschning, Carsten J., Zhou, Rongbin

المصدر: Frontiers in Immunology ; volume 13 ; ISSN 1664-3224

مصطلحات موضوعية: Immunology, Immunology and Allergy

الإتاحة: https://doi.org/10.3389/fimmu.2022.857929Test

المؤلفون: Kibler, Artur, Budeus, Bettina, Homp, Ekaterina, Bronischewski, Kevin, Berg, Victoria, Sellmann, Ludger, Murke, Florian, Heinold, Andreas, Heinemann, Falko Markus, Lindemann, Monika, Bekeredjian-Ding, Isabelle, Horn, Peter, Kirschning, Carsten, Küppers, Ralf, Seifert, Marc

المصدر: Journal of experimental medicine, 218(4):e20201952

مصطلحات موضوعية: Experimentelle Medizin

الوصف: Human memory B cells (MBCs) are generated and diversified in secondary lymphoid tissues throughout the organism. A paired immunoglobulin (Ig)-gene repertoire analysis of peripheral blood (PB) and splenic MBCs from infant, adult, and elderly humans revealed that throughout life, circulating MBCs are comprehensively archived in the spleen. Archive MBC clones are systematically preserved and uncoupled from class-switching. Clonality in the spleen increases steadily, but boosts at midlife, thereby outcompeting small clones. The splenic marginal zone (sMZ) represents a primed MBC compartment, generated from a stochastic exchange within the archive memory pool. This is supported by functional assays, showing that PB and splenic CD21+ MBCs acquire transient CD21high expression upon NOTCH2-stimulation. Our study provides insight that the human MBC system in PB and spleen is composed of three interwoven compartments: the dynamic relationship of circulating, archive, and its subset of primed (sMZ) memory changes with age, thereby contributing to immune aging.

العلاقة: https://repository.publisso.de/resource/frl:6431953Test; https://doi.org/10.1084/jem.20201952Test; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868796Test

الإتاحة: https://doi.org/10.1084/jem.20201952Test
https://repository.publisso.de/resource/frl:6431953Test
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868796Test

المؤلفون: Michelsen, Kathrin S., Aicher, Alexandra, Mohaupt, Mariette, Hartung, Thomas, Dimmeler, Stefanie, Kirschning, Carsten Jürgen, Schumann, Ralf R.

مصطلحات موضوعية: ddc:610

الوصف: Toll-like receptors (TLRs) have been found to be key elements in pathogen recognition by the host immune system. Dendritic cells (DCs) are crucial for both innate immune responses and initiation of acquired immunity. Here we focus on the potential involvement of TLR ligand interaction in DC maturation. TLR2 knockout mice and mice carrying a TLR4 mutation (C3H/HeJ) were investigated for DC maturation induced by peptidoglycan (PGN), lipopolysaccharide (LPS), or lipoteichoic acids (LTAs). All stimuli induced maturation of murine bone marrow-derived DCs in control mice. TLR2−/− mice lacked maturation upon stimulation with PGN, as assessed by expression of major histocompatibility complex class II, CD86, cytokine, and chemokine production, fluorescein isothiocyanate-dextran uptake, and mixed lymphocyte reactions, while being completely responsive to LPS. A similar lack of maturation was observed in C3H/HeJ mice upon stimulation with LPS. DC maturation induced by LTAs from two different types of bacteria was severely impaired in TLR2−/−, whereas C3H/HeJ mice responded to LTAs in a manner similar to wild-type mice. We demonstrate that DC maturation is induced by stimuli from Gram-positive microorganisms, such as PGN and LTA, with similar efficiency as by LPS. Finally, we provide evidence that TLR2 and TLR4 interaction with the appropriate ligand is essential for bacteria-induced maturation of DCs.

وصف الملف: application/pdf

العلاقة: http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/75937Test; urn:nbn:de:hebis:30:3-759373; https://nbn-resolving.org/urn:nbn:de:hebis:30:3-759373Test; https://doi.org/10.1074/jbc.M011615200Test; http://publikationen.ub.uni-frankfurt.de/files/75937/1-s2.0-S0021925819301097-main.pdfTest

الإتاحة: https://doi.org/10.1074/jbc.M011615200Test
http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/75937Test
https://nbn-resolving.org/urn:nbn:de:hebis:30:3-759373Test
http://publikationen.ub.uni-frankfurt.de/files/75937/1-s2.0-S0021925819301097-main.pdfTest

المؤلفون: Li, Qian, Wang, Jun, Islam, Heba, Kirschning, Carsten, Lu, Hongzhou, Hoffmann, Daniel, Dittmer, Ulf, Lu, Mengji

المصدر: Cell Death & Disease ; volume 12, issue 1 ; ISSN 2041-4889

مصطلحات موضوعية: Cancer Research, Cell Biology, Cellular and Molecular Neuroscience, Immunology

الوصف: Host immune control plays a pivotal role in resolving primary hepatitis-B-virus (HBV) infections. The complex interaction between HBV and host immune cells, however, remains unclear. In this study, the transcriptional profiling of specimens from animals infected with woodchuck hepatitis virus (WHV) indicated TLR2 mRNA accumulation as most strongly impacted during WHV infection resolution as compared to other mRNAs. Analysis of blood transcriptional modules demonstrated that monocytes and B-cells were the predominantly activated cell types in animals that showed resolution of infection, which was similar to the response of TLR2-stimulated PBMCs. Further investigation of TLR2-stimulated B-cells pointed at interactions between activated TLR signaling, Akt-mTOR, and glucose metabolic pathways. Moreover, analysis of B-cells from Tlr2 −/− , Trif −/− , Myd88 −/− , and Trif/Myd88 −/− mice challenged with HBV particles indicated B-cell function and glucose metabolism alterations is TLR2-MyD88-mTOR axis dependent. Overall, our study implicates B-cell TLR2 activation in HBV infection resolution.

الإتاحة: https://doi.org/10.1038/s41419-020-03284-1Test
https://www.nature.com/articles/s41419-020-03284-1.pdfTest
https://www.nature.com/articles/s41419-020-03284-1Test