Publications by authors named "Laura Mittmann"

9 Publications

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Uncoupled biological and chronological aging of neutrophils in cancer promotes tumor progression.

J Immunother Cancer 2021 12;9(12)

Department of Otorhinolaryngology, LMU München, Munich, Germany

Background: Beyond their fundamental role in homeostasis and host defense, neutrophilic granulocytes (neutrophils) are increasingly recognized to contribute to the pathogenesis of malignant tumors. Recently, aging of mature neutrophils in the systemic circulation has been identified to be critical for these immune cells to properly unfold their homeostatic and anti-infectious functional properties. The role of neutrophil aging in cancer remains largely obscure.

Methods: Employing advanced in vivo microscopy techniques in different animal models of cancer as well as utilizing pulse-labeling and cell transfer approaches, various / assays, and human data, we sought to define the functional relevance of neutrophil aging in cancer.

Results: Here, we show that signals released during early tumor growth accelerate biological aging of circulating neutrophils, hence uncoupling biological from chronological aging of these immune cells. This facilitates the accumulation of highly reactive neutrophils in malignant lesions and endows them with potent protumorigenic functions, thus promoting tumor progression. Counteracting uncoupled biological aging of circulating neutrophils by blocking the chemokine receptor CXCR2 effectively suppressed tumor growth.

Conclusions: Our data uncover a self-sustaining mechanism of malignant neoplasms in fostering protumorigenic phenotypic and functional changes in circulating neutrophils. Interference with this aberrant process might therefore provide a novel, already pharmacologically targetable strategy for cancer immunotherapy.
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http://dx.doi.org/10.1136/jitc-2021-003495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8655594PMC
December 2021

Binding of Rap1 and Riam to Talin1 Fine-Tune β2 Integrin Activity During Leukocyte Trafficking.

Front Immunol 2021 19;12:702345. Epub 2021 Aug 19.

Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine, Technische Universität München, Munich, Germany.

β2 integrins mediate key processes during leukocyte trafficking. Upon leukocyte activation, the structurally bent β2 integrins change their conformation towards an extended, intermediate and eventually high affinity conformation, which mediate slow leukocyte rolling and firm arrest, respectively. Translocation of talin1 to integrin adhesion sites by interactions with the small GTPase Rap1 and the Rap1 effector Riam precede these processes. Using Rap1 binding mutant talin1 and Riam deficient mice we show a strong Riam-dependent T cell homing process to lymph nodes in adoptive transfer experiments and by intravital microscopy. Moreover, neutrophils from compound mutant mice exhibit strongly increased rolling velocities to inflamed cremaster muscle venules compared to single mutants. Using Hoxb8 cell derived neutrophils generated from the mutant mouse strains, we show that both pathways regulate leukocyte rolling and adhesion synergistically by inducing conformational changes of the β2 integrin ectodomain. Importantly, a simultaneous loss of both pathways results in a rolling phenotype similar to talin1 deficient neutrophils suggesting that β2 integrin regulation primarily occurs these two pathways.
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http://dx.doi.org/10.3389/fimmu.2021.702345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417109PMC
December 2021

C81-evoked inhibition of the TNFR1-NFκB pathway during inflammatory processes for stabilization of the impaired vascular endothelial barrier for leukocytes.

FASEB J 2021 06;35(6):e21656

Institute of Pharmaceutical Biology, Goethe University, Frankfurt/Main, Germany.

Chronic inflammation-related diseases are characterized by persistent leukocyte infiltration into the underlying tissue. The vascular endothelium plays a major role in this pathophysiological condition. Only few therapeutic strategies focus on the vascular endothelium as a major target for an anti-inflammatory approach. In this study, we present the natural compound-derived carbazole derivative C81 as chemical modulator interfering with leukocyte-endothelial cell interactions. An in vivo assay employing intravital microscopy to monitor leukocyte trafficking after C81 treatment in postcapillary venules of a murine cremaster muscle was performed. Moreover, in vitro assays using HUVECs and monocytes were implemented. The impact of C81 on cell adhesion molecules and the NFκB signaling cascade was analyzed in vitro in endothelial cells. Effects of C81 on protein translation were determined by incorporation of a puromycin analog-based approach and polysome profiling. We found that C81 significantly reduced TNF-activated leukocyte trafficking in postcapillary venules. Similar results were obtained in vitro when C81 reduced leukocyte-endothelial cell interactions by down-regulating cell adhesion molecules. Focusing on the NFκB signaling cascade, we found that C81 reduced the activation on multiple levels of the cascade through promoted IκBα recovery by attenuation of IκBα ubiquitination and through reduced protein levels of TNFR1 caused by protein translation inhibition. We suggest that C81 might represent a promising lead compound for interfering with inflammation-related processes in endothelial cells by down-regulation of IκBα ubiquitination on the one hand and inhibition of translation on the other hand without exerting cytotoxic effects.
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http://dx.doi.org/10.1096/fj.202100037RDOI Listing
June 2021

Vitronectin stabilizes intravascular adhesion of neutrophils by coordinating β2 integrin clustering.

Haematologica 2021 10 1;106(10):2641-2653. Epub 2021 Oct 1.

Walter Brendel Centre of Experimental Medicine and Klinikum der Universität Munchen, Germany.

The recruitment of neutrophils from the microvasculature to the site of injury or infection represents a key event in the inflammatory response. Vitronectin (VN) is a multifunctional macromolecule abundantly present in blood and extracellular matrix. The role of this glycoprotein in the extravasation process of circulating neutrophils remains elusive. Employing advanced in vivo/ex vivo imaging techniques in different mouse models as well as in vitro methods, we uncovered a previously unrecognized function of VN in the transition of dynamic to static intravascular interactions of neutrophils with microvascular endothelial cells. These distinct properties of VN require the heteromerization of this glycoprotein with plasminogen activator inhibitor-1 (PAI- 1) on the activated venular endothelium and subsequent interactions of this protein complex with the scavenger receptor low-density lipoprotein receptor-related protein-1 on intravascularly adhering neutrophils. This induces p38 mitogen-activated protein kinases-dependent intracellular signaling events which, in turn, regulates the proper clustering of the b2 integrin lymphocyte function associated antigen-1 on the surface of these immune cells. As a consequence of this molecular interplay, neutrophils become able to stabilize their adhesion to the microvascular endothelium and, subsequently, to extravasate to the perivascular tissue. Hence, endothelial-bound VN-PAI-1 heteromers stabilize intravascular adhesion of neutrophils by coordinating b2 integrin clustering on the surface of these immune cells, thereby effectively controlling neutrophil trafficking to inflamed tissue. Targeting this protein complex might be beneficial for the prevention and treatment of inflammatory pathologies.
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http://dx.doi.org/10.3324/haematol.2019.226241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485676PMC
October 2021

GDF15 promotes simultaneous astrocyte remodeling and tight junction strengthening at the blood-brain barrier.

J Neurosci Res 2020 07 13;98(7):1433-1456. Epub 2020 Mar 13.

Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany.

Perivascular astrocyte processes (PAP) surround cerebral endothelial cells (ECs) and modulate the strengthening of tight junctions to influence blood-brain barrier (BBB) permeability. Morphologically altered astrocytes may affect barrier properties and trigger the onset of brain pathologies. However, astrocyte-dependent mediators of these events remain poorly studied. Here, we show a pharmacologically driven elevated expression and release of growth/differentiation factor 15 (GDF15) in rat primary astrocytes and cerebral PAP. GDF15 has been shown to possess trophic properties for motor neurons, prompting us to hypothesize similar effects on astrocytes. Indeed, its increased expression and release occurred simultaneously to morphological changes of astrocytes in vitro and PAP, suggesting modulatory effects of GDF15 on these cells, but also neighboring EC. Administration of recombinant GDF15 was sufficient to promote astrocyte remodeling and enhance barrier properties between ECs in vitro, whereas its pharmacogenetic abrogation prevented these effects. We validated our findings in male high anxiety-related behavior rats, an animal model of depressive-like behavior, with shrunk PAP associated with reduced expression of the junctional protein claudin-5, which were both restored by a pharmacologically induced increase in GDF15 expression. Thus, we identified GDF15 as an astrocyte-derived trigger of astrocyte process remodeling linked to enhanced tight junction strengthening at the BBB.
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http://dx.doi.org/10.1002/jnr.24611DOI Listing
July 2020

Metabotropic glutamate receptor subtype 7 controls maternal care, maternal motivation and maternal aggression in mice.

Genes Brain Behav 2020 01 14;19(1):e12627. Epub 2019 Dec 14.

Department of Behavioural and Molecular Neurobiology, University of Regensburg, Regensburg, Germany.

The group III metabotropic glutamate receptor subtype 7 (mGlu7) is an important regulator of glutamatergic and GABAergic neurotransmission and known to mediate emotionality and male social behavior. However, a possible regulatory role in maternal behavior remains unknown to date. Adequate expression of maternal behavior is essential for successful rearing and healthy development of the young. By understanding genetic and neural mechanisms underlying this important prosocial behavior, we gain valuable insights into possible dysregulations. Using genetic ablation as well as pharmacological modulation, we studied various parameters of maternal behavior in two different mouse strains under the influence of mGlu7. We can clearly show a regulatory role of mGlu7 in maternal behavior. Naïve virgin female C57BL/6 mGlu7 knockout mice showed more often nursing postures and less spontaneous maternal aggression compared to their heterozygous and wildtype littermates. In lactating C57BL/6 wildtype mice, acute central activation of mGlu7 by the selective agonist AMN082 reduced arched back nursing and accelerated pup retrieval without affecting maternal aggression. In addition, in lactating CD1 wildtype mice the selective mGlu7 antagonist XAP044 increased both pup retrieval and maternal aggression. With respect to receptor expression levels, mGlu7 mRNA expression was higher in lactating vs virgin C57BL/6 mice in the prefrontal cortex, but not hypothalamus or hippocampus. In conclusion, these findings highlight a significant role of the mGlu7 receptor subtype in mediating maternal behavior in mice. Region-dependent studies are warranted to further extend our knowledge on the specific function of the brain glutamate system in maternal behavior.
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http://dx.doi.org/10.1111/gbb.12627DOI Listing
January 2020

Neutrophils promote venular thrombosis by shaping the rheological environment for platelet aggregation.

Sci Rep 2019 11 4;9(1):15932. Epub 2019 Nov 4.

Walter Brendel Centre of Experimental Medicine, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.

In advanced inflammatory disease, microvascular thrombosis leads to the interruption of blood supply and provokes ischemic tissue injury. Recently, intravascularly adherent leukocytes have been reported to shape the blood flow in their immediate vascular environment. Whether these rheological effects are relevant for microvascular thrombogenesis remains elusive. Employing multi-channel in vivo microscopy, analyses in microfluidic devices, and computational modeling, we identified a previously unanticipated role of leukocytes for microvascular clot formation in inflamed tissue. For this purpose, neutrophils adhere at distinct sites in the microvasculature where these immune cells effectively promote thrombosis by shaping the rheological environment for platelet aggregation. In contrast to larger (lower-shear) vessels, this process in high-shear microvessels does not require fibrin generation or extracellular trap formation, but involves GPIbα-vWF and CD40-CD40L-dependent platelet interactions. Conversely, interference with these cellular interactions substantially compromises microvascular clotting. Thus, leukocytes shape the rheological environment in the inflamed venular microvasculature for platelet aggregation thereby effectively promoting the formation of blood clots. Targeting this specific crosstalk between the immune system and the hemostatic system might be instrumental for the prevention and treatment of microvascular thromboembolic pathologies, which are inaccessible to invasive revascularization strategies.
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http://dx.doi.org/10.1038/s41598-019-52041-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828708PMC
November 2019

Direct Rap1/Talin1 interaction regulates platelet and neutrophil integrin activity in mice.

Blood 2018 12 15;132(26):2754-2762. Epub 2018 Nov 15.

Department Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany.

Targeting Talin1 to the plasma membrane is a crucial step in integrin activation, which in leukocytes is mediated by a Rap1/RIAM/Talin1 pathway, whereas in platelets, it is RIAM independent. Recent structural, biochemical, and cell biological studies have suggested direct Rap1/Talin1 interaction as an alternative mechanism to recruit Talin1 to the membrane and induce integrin activation. To test whether this pathway is of relevance in vivo, we generated Rap1 binding-deficient Talin1 knockin (Tln1) mice. Although Tln1 mice showed no obvious abnormalities, their platelets exhibited reduced integrin activation, aggregation, adhesion, and spreading, resulting in prolonged tail-bleeding times and delayed thrombus formation and vessel occlusion in vivo. Surprisingly, neutrophil adhesion to different integrin ligands and β2 integrin-dependent phagocytosis were also significantly impaired, which caused profound leukocyte adhesion and extravasation defects in Tln1 mice. In contrast, macrophages exhibited no defect in adhesion or spreading despite reduced integrin activation. Taken together, our findings suggest that direct Rap1/Talin1 interaction is of particular importance in regulating the activity of different integrin classes expressed on platelets and neutrophils, which both depend on fast and dynamic integrin-mediated responses.
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http://dx.doi.org/10.1182/blood-2018-04-846766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307989PMC
December 2018

Plasminogen Activator Inhibitor-1 Promotes Neutrophil Infiltration and Tissue Injury on Ischemia-Reperfusion.

Arterioscler Thromb Vasc Biol 2018 04 25;38(4):829-842. Epub 2018 Jan 25.

From the Walter Brendel Centre of Experimental Medicine (M.P., G.Z., M.H., B.U., J.S., L.M., M.F., D.F., M.L., A.K., F.K., C.A.R.), Department of Otorhinolaryngology (G.Z., M.H., B.U., C.A.R.), Head and Neck Surgery (M.P.), Pharmaceutical Biology, Department of Pharmacy, Center for Drug Research (S.Z.), Department of Surgery (D.F., M.L., A.K.), and Department of Radiation Oncology (K.L.), Ludwig-Maximilians-Universität München, Munich, Germany; Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Germany (M.P); Institute of Pharmaceutical Biology, Goethe University Frankfurt, Germany (R.F.); and Institute of Basic Medical Sciences, University of Oslo, Norway (S.K.).

Objective: Ischemia-reperfusion (I/R) injury significantly contributes to organ dysfunction and failure after myocardial infarction, stroke, and transplantation. In addition to its established role in the fibrinolytic system, plasminogen activator inhibitor-1 has recently been implicated in the pathogenesis of I/R injury. The underlying mechanisms remain largely obscure.

Approach And Results: Using different in vivo microscopy techniques as well as ex vivo analyses and in vitro assays, we identified that plasminogen activator inhibitor-1 rapidly accumulates on microvascular endothelial cells on I/R enabling this protease inhibitor to exhibit previously unrecognized functional properties by inducing an increase in the affinity of β2 integrins in intravascularly rolling neutrophils. These events are mediated through low-density lipoprotein receptor-related protein-1 and mitogen-activated protein kinase-dependent signaling pathways that initiate intravascular adherence of these immune cells to the microvascular endothelium. Subsequent to this process, extravasating neutrophils disrupt endothelial junctions and promote the postischemic microvascular leakage. Conversely, deficiency of plasminogen activator inhibitor-1 effectively reversed leukocyte infiltration, microvascular dysfunction, and tissue injury on experimental I/R without exhibiting side effects on microvascular hemostasis.

Conclusions: Our experimental data provide novel insights into the nonfibrinolytic properties of the fibrinolytic system and emphasize plasminogen activator inhibitor-1 as a promising target for the prevention and treatment of I/R injury.
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http://dx.doi.org/10.1161/ATVBAHA.117.309760DOI Listing
April 2018
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