Julia Kzhyshkowska

Heidelberg University

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Alexei Gratchev

Ministry of Health of the Russian Federation

Sergij Goerdt

University Hospital Heidelberg

НВ

Н. В. Чердынцева

National Research Tomsk State University

Irina Larionova

Tomsk National Research Medical Center

Vladimir Riabov

University Hospital Heidelberg

Harald Klüter

Heidelberg University

Kai Schledzewski

University Medical Centre Mannheim

Christina Schmuttermaier

Heidelberg University

V. V. Ryabov

Tomsk National Research Medical Center

МV

М. V. Zavyalova

Siberian State Medical University

Cooperative Institutions

Heidelberg University

201

University Hospital Heidelberg

164

Russian Academy of Sciences

145

University Medical Centre Mannheim

122

National Research Tomsk State University

102

Tomsk National Research Medical Center

University College London

Imperial College London

Leiden University Medical Center

Inserm

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Expression of M2 macrophage markers YKL-39 and CCL18 in breast cancer is associated with the effect of neoadjuvant chemotherapy

Cancer Chemotherapy and Pharmacology (2018)

Н. В. Литвяков М. М. Цыганов Irina Larionova М. К. Ибрагимова I. V. Deryusheva

CD68

CCL18

10.1007/s00280-018-3594-8

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Citations (36)

Autologous Lipofilling Improves Clinical Outcome in Patients With Symptomatic Dermal Scars Through Induction of a Pro-Regenerative Immune Response

Aesthetic Surgery Journal (2021)

Maroesjka Spiekman Delia L Francia Dieuwertje M. Mossel Linda A. Brouwer Gilles F.H. Diercks

Autologous lipofilling is an emerging procedure to treat and possibly reverse dermal scars and to reduce scar-related pain, but its efficacy and mechanisms are poorly understood.The aim of this study was to test the hypothesis that repeated lipografts reverse dermal scars by reinitiation of wound healing.In a prospective, non-placebo-controlled clinical study, 27 adult patients with symptomatic scars were given 2 lipofilling treatments at 3-month intervals. As primary outcome, clinical effects were measured with the Patient and Observer Scar Assessment Scale (POSAS). Scar biopsies were taken before and after treatments to assess scar remodeling at a cellular level.Twenty patients completed the study. Patients' scars improved after lipofilling. The total POSAS scores (combined patient and observer scores) decreased from 73.2 [14.7] points (mean [standard deviation]) pretreatment to 46.1 [14.0] and 32.3 [13.2] points after the first and second lipofilling treatment, respectively. Patient POSAS scores decreased from 37.3 [8.8] points to 27.2 [11.3] and 21.1 [11.4] points, whereas observer POSAS scores decreased from 35.9 [9.5] points to 18.9 [6.0] and 11.3 [4.5] points after the first and second treatment, respectively. After each lipofilling treatment, T lymphocytes, mast cells, and M2 macrophages had invaded scar tissue and were associated with increased vascularization. In addition, the scar-associated epidermis showed an increase in epidermal cell proliferation to levels similar to that normal in skin. Moreover, lipofilling treatment caused normalization of the extracellular matrix organization towards that of normal skin.Autologous lipofilling improves the clinical outcome of dermal scars through the induction of a pro-regenerative immune response, increased vascularization, and epidermal proliferation and remodeling of scar tissue extracellular matrix.

10.1093/asj/sjab280

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Citations (7)

Wnt2 acts as a cell type-specific, autocrine growth factor in rat hepatic sinusoidal endothelial cells cross-stimulating the VEGF pathway

Hepatology (2008)

Diana Klein Alexandra Demory Francis Peyre Jens Krøll Hellmut G. Augustin

The mechanisms regulating the growth and differentiation of hepatic sinusoidal endothelial cells (HSECs) are not well defined. Because Wnt signaling has become increasingly important in developmental processes such as vascular and hepatic differentiation, we analyzed HSEC-specific Wnt signaling in detail. Using highly pure HSECs isolated by a newly developed protocol selecting against nonsinusoidal hepatic endothelial cells, we comparatively screened the multiple components of the Wnt pathway for differential expression in HSECs and lung microvascular endothelial cells (LMECs) via reverse-transcription polymerase chain reaction (RT-PCR). As confirmed via quantitative RT-PCR and northern and western blotting experiments, Wnt2 (and less so Wnt transporter wls/evi) and Wnt coreceptor Ryk were overexpressed by HSECs, whereas Wnt inhibitory factor (WIF) was strongly overexpressed by LMECs. Exogenous Wnt2 superinduced proliferation of HSECs ( P < 0.05). The Wnt inhibitor secreted frizzled-related protein 1 (sFRP1) ( P < 0.005) and transfection of HSECs with Wnt2 small interfering RNA (siRNA) reduced proliferation of HSECs. These effects were rescued by exogenous Wnt2. Tube formation of HSECs on matrigel was strongly inhibited by Wnt inhibitors sFRP1 and WIF ( P < 0.0005). Wnt signaling in HSECs activated the canonical pathway inducing nuclear translocation of β-catenin. GST (glutathione transferase) pull-down and co-immunoprecipitation assays showed Fzd4 to be a novel Wnt2 receptor in HSECs. Gene profiling identified vascular endothelial growth factor receptor-2 (VEGFR-2) as a target of Wnt2 signaling in HSECs. Inhibition of Wnt signaling down-regulated VEGFR-2 messenger RNA and protein. Wnt2 siRNA knock-down confirmed Wnt2 specificity of VEGFR-2 regulation in HSECs. Conclusion: Wnt2 is an autocrine growth and differentiation factor specific for HSECs that synergizes with the VEGF signaling pathway to exert its effects.

10.1002/hep.22084

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Citations (100)

Phosphatidylinositide 3-kinase activity is required for stabilin-1-mediated endosomal transport of acLDL

Immunobiology (2005)

Julia Kzhyshkowska Alexei Gratchev Heike Brundiers Srinivas Mamidi Liis Krusell

Wortmannin

10.1016/j.imbio.2005.05.022

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Citations (52)

Cytostatic cancer therapy modulates monocyte-macrophage cell functions: how it impacts on treatment outcomes

Experimental Oncology (2019)

М. Р. Патышева M. N. Stakheyeva Irina Larionova A. A. Fedorov Julia Kzhyshkowska

Macrophages are important effectors of innate immunity and the key component of the tumor microenvironment strongly influencing cancer disease outcome and efficiency of cancer therapy. Moreover, recent data have shown that monocytes as macrophage precursors can impact on tumor ability to progression. It's well known that although tumor-associated macrophages consist of diverse populations, in general, they have tumor-supporting activity. To change tumor-supporting state of tumor-associated macrophages toward tumor-inhibiting mode is one of prospective aims of modern cancer immunotherapy. Cytostatics seems to be possible tools to achieve this aim, because recently it has been shown that chemo- and radiotherapy possess immunomodulatory effects. Most of the findings are related to lymphocytes - T-lymphocytes and NK-cells, but not to monocyte/macrophage lineage. In the review, we have analyzed how cytostatic drugs influence the properties of monocyte/macrophage lineage cells to prospect using of chemotherapy to enhance their antitumor activity.

Monocyte

Cancer Immunotherapy

10.32471/exp-oncology.2312-8852.vol-41-no-3.13597

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Citations (3)

Perspectives for Monocyte/Macrophage-Based Diagnostics of Chronic Inflammation

Transfusion Medicine and Hemotherapy (2016)

Julia Kzhyshkowska Alexandru Gudima Kondaiah Moganti Alexei Gratchev Alexander N. Orekhov

Low-grade chronic inflammation underlies the development of the most dangerous cardiometabolic disorders including type 2 diabetes and its vascular complications. In contrast to acute inflammation induced by bacteria and viruses, chronic inflammation can be driven by abnormal reaction to endogenous factors, including Th2 cytokines, metabolic factors like advanced glycation end products (AGEs), modified lipoproteins, or hyperglycemia. The key innate immune cells that recognize these factors in blood circulation are monocytes. Inflammatory programming of monocytes which migrate into tissues can, in turn, result into generation of tissue macrophages with pathological functions. Therefore, determination of the molecular and functional phenotype of circulating monocytes is a very promising diagnostic tool for the identification of hidden inflammation, which can precede the development of the pathology. Here we propose a new test system for the identification of inflammatory programming of monocytes: surface biomarkers and ex vivo functional system. We summarize the current knowledge about surface biomarkers for monocyte subsets, including CD16, CCR2, CX3CR1, CD64, stabilin-1 and CD36, and their association with inflammatory human disorders. Furthermore, we present the design of an ex vivo monocyte-based test system with minimal set of parameters as a potential diagnostic tool for the identification of personalized inflammatory responses.

CCR2

Monocyte

Ex vivo

CD64

10.1159/000444943

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Citations (47)

New insights into the role of the CHI3L2 protein in invasive ductal breast carcinoma

Scientific Reports (2024)

Agnieszka Rusak Ewa Kątnik Tomasz Górnicki Christina Schmuttermaier Krzysztof Kujawa

Abstract Chitinase-like proteins have multiple biological functions that promote tumor growth, angiogenesis and metastasis. Expression of CHI3L2, which is similar in structure to CHI3L1, is detected in glioma cells and tumor-associated macrophages (TAMs) in glioma and breast cancer. However, its exact role remains unclear. We analyzed the expression of CHI3L2 in 74 invasive ductal breast carcinoma (IDC) tumors, breast cancer and macrophages cell cultures using immunohistochemistry, immunofluorescence, Western blot and PCR methods. Clinicopathologic data were included in the analysis. The results obtained show that CHI3L2 expression decreases with increasing degree of tumor grade and negative status of estrogen (ER) and progesterone receptors (PR). Furthermore, CHI3L2 is significantly and positively correlated with phosphorylation of STAT-3 and ERK1/2 signaling pathways, but negatively correlated with macrophage infiltration. CHI3L2 is expressed both in the cytoplasm of cancer cells and in macrophages and may regulate STAT-3 and ERK1/2 phosphorylation in breast cancer cell lines. Analysis of the clinicopathologic data revealed that CHI3L2 levels had no effect on patient survival. CHI3L2 expression may be specific for cancer cells in IDC and involved in cross-talk with the tumor microenvironment. Our study has shown that IDC cancer cells express the CHI3L2 protein, possibly indicating a novel function of this protein.

Immunofluorescence

Breast carcinoma

10.1038/s41598-024-77930-5

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Titanium Nanoparticles Enhance Production and Suppress Stabilin-1-Mediated Clearance of GDF-15 in Human Primary Macrophages

Frontiers in Immunology (2021)

Lina Silva-Bermudez Tatyana Sevastyanova Christina Schmuttermaier Carolina De La Torre Leonie Schumacher

Macrophages are key innate immune cells that mediate implant acceptance or rejection. Titanium implants degrade over time inside the body, which results in the release of implant wear-off particles. Titanium nanoparticles (TiNPs) favor pro-inflammatory macrophage polarization (M1) and lower tolerogenic activation (M2). GDF-15 regulates immune tolerance and fibrosis and is endocytosed by stabilin-1. How TiNPs affect the healing activities of macrophages and their release of circulating cytokines is an open question in regenerative medicine. In this study for the first time, we identified the transcriptional program induced and suppressed by TiNPs in human pro-inflammatory and healing macrophages. Microarray analysis revealed that TiNPs altered the expression of 5098 genes in M1 (IFN-γ-stimulated) and 4380 genes in M2 (IL-4-stimulated) macrophages. 1980 genes were differentially regulated in both M1 and M2. Affymetrix analysis, confirmed by RT-PCR, demonstrated that TiNPs upregulate expression of GDF-15 and suppress stabilin-1, scavenger receptor of GDF-15. TiNPs also significantly stimulated GDF-15 protein secretion in inflammatory and healing macrophages. Flow cytometry demonstrated, that scavenging activity of stabilin-1 was significantly suppressed by TiNPs. Confocal microscopy analysis showed that TiNPs impair internalization of stabilin-1 ligand acLDL and its transport to the endocytic pathway. Our data demonstrate that TiNPs have a dual effect on the GDF-15/stabilin-1 interaction in macrophage system, by increasing the production of GDF-15 and suppressing stabilin-1-mediated clearance function. In summary, this process can result in a significant increase of GDF-15 in the extracellular space and in circulation leading to unbalanced pro-fibrotic reactions and implant complications.

Internalization

Proinflammatory cytokine

Scavenger Receptor

Mannose receptor

10.3389/fimmu.2021.760577

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Citations (12)

TGF-BETA INDUCES ATHEROSCLEROTIC PROGRAM IN MATURE HUMAN MACROPHAGES

Atherosclerosis Supplements (2008)

Alexei Gratchev Julia Kzhyshkowska Sheila Kannookadan Miriam Ochsenreiter А. Н. Попова

Morin

10.1016/s1567-5688(08)70034-5

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Citations (0)

Effect of increased glucose on the expression of TLRs in human macrophages: potential mechanism of chronic inflammation in diabetes

Diabetologie und Stoffwechsel (2015)

Michael Balduff Kondaiah Moganti F Li Harald Klüter Martin C. Harmsen

Diabetic patients suffer from a chronic inflammation regulated by macrophages. M1 and M2 represent two major directions of macrophage functional polarisation. Toll-like receptors (TLR)-mediated response to exogenous and endogenous factors results in pro-inflammatory activation of macrophages. Increased TLR expression in monocytes is associated with the diabetic inflammation and complications. The aim of our study was to examine how elevated glucose levels affect expression of TLRs in M1 and M2. Monocytes were isolated from healthy donors and cultured in serum-free medium in the presence of 5mM or 25mM glucose for 6 days. M1 and M2 differentiation was driven by IFN-γ and IL-4. Quantification of TLR mRNA expression was performed by RT-PCR and demonstrated that mRNA of TLR1, 2, 4, 6 and 8, but not TLR5 and 9, were expressed in M1 and M2. All identified TLRs were expressed on higher levels in M1 compared to M2 in low and high glucose conditions. Increased glucose had most pronounced stimulatory effect on the expression of TLR2 and less on TLR6. In individual M1 cultures high glucose stimulated up to 8-fold increase of TLR2 and up to 28% increased of TLR6 expression. In M2, TLR2 expression was up to 6-fold higher in the presence to high glucose. High glucose had suppressive effect on the expression of TLR4 (in 5 of 8 donors up to 65%) in M1 and M2. We concluded that glucose regulates TLR2, 6 and 4 expression in a donor-specific way. This may explain the individual development of inflammation-mediated complications in diabetes.

10.1055/s-0035-1549579

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Citations (0)