Publications by authors named "Kathrin Nussbaum"

6 Publications

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Sirt6 deletion in bone marrow-derived cells increases atherosclerosis - Central role of macrophage scavenger receptor 1.

J Mol Cell Cardiol 2020 02 21;139:24-32. Epub 2020 Jan 21.

Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland; Department of Cardiology, University Heart Center, Zurich University Hospital, Zurich, Switzerland. Electronic address:

Aims: Sirtuin 6 (Sirt6) is a NAD-dependent deacetylase that plays a key role in DNA repair, inflammation and lipid regulation. Sirt6-null mice show severe metabolic defects and accelerated aging. Macrophage-foam cell formation via scavenger receptors is a key step in atherogenesis. We determined the effects of bone marrow-restricted Sirt6 deletion on foam cell formation and atherogenesis using a mouse model.

Methods And Results: Sirt6 deletion in bone marrow-derived cells increased aortic plaques, lipid content and macrophage numbers in recipient Apoe mice fed a high-cholesterol diet for 12 weeks (n = 12-14, p < .001). In RAW macrophages, Sirt6 overexpression reduced oxidized low-density lipoprotein (oxLDL) uptake, Sirt6 knockdown enhanced it and increased mRNA and protein levels of macrophage scavenger receptor 1 (Msr1), whereas levels of other oxLDL uptake and efflux transporters remained unchanged. Similarly, in human primary macrophages, Sirt6 knockdown increased MSR1 protein levels and oxLDL uptake. Double knockdown of Sirt6 and Msr1 abolished the increase in oxLDL uptake observed upon Sirt6 single knockdown. FACS analyses of macrophages from aortic plaques of Sirt6-deficient bone marrow-transplanted mice showed increased MSR1 protein expression. Double knockdown of Sirt6 and the transcription factor c-Myc in RAW cells abolished the increase in Msr1 mRNA and protein levels; c-Myc overexpression increased Msr1 mRNA and protein levels.

Conclusions: Loss of Sirt6 in bone marrow-derived cells is proatherogenic; hereby macrophages play an important role given a c-Myc-dependent increase in MSR1 protein expression and an enhanced oxLDL uptake in human and murine macrophages. These findings assign endogenous SIRT6 in macrophages an important atheroprotective role.
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http://dx.doi.org/10.1016/j.yjmcc.2020.01.002DOI Listing
February 2020

Cell engineering with microfluidic squeezing preserves functionality of primary immune cells in vivo.

Proc Natl Acad Sci U S A 2018 11 31;115(46):E10907-E10914. Epub 2018 Oct 31.

SQZ Biotechnologies, Watertown, MA 02472.

The translational potential of cell-based therapies is often limited by complications related to effectively engineering and manufacturing functional cells. While the use of electroporation is widespread, the impact of electroporation on cell state and function has yet to be fully characterized. Here, we use a genome-wide approach to study optimized electroporation treatment and identify striking disruptions in the expression profiles of key functional transcripts of human T cells. These genetic disruptions result in concomitant perturbation of cytokine secretion including a 648-fold increase in IL-2 secretion ( < 0.01) and a 30-fold increase in IFN-γ secretion ( < 0.05). Ultimately, the effects at the transcript and protein level resulted in functional deficiencies in vivo, with electroporated T cells failing to demonstrate sustained antigen-specific effector responses when subjected to immunological challenge. In contrast, cells subjected to a mechanical membrane disruption-based delivery mechanism, cell squeezing, had minimal aberrant transcriptional responses [0% of filtered genes misregulated, false discovery rate (FDR) q < 0.1] relative to electroporation (17% of genes misregulated, FDR q < 0.1) and showed undiminished effector responses, homing capabilities, and therapeutic potential in vivo. In a direct comparison of functionality, T cells edited for PD-1 via electroporation failed to distinguish from untreated controls in a therapeutic tumor model, while T cells edited with similar efficiency via cell squeezing demonstrated the expected tumor-killing advantage. This work demonstrates that the delivery mechanism used to insert biomolecules affects functionality and warrants further study.
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http://dx.doi.org/10.1073/pnas.1809671115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6243275PMC
November 2018

Tissue microenvironment dictates the fate and tumor-suppressive function of type 3 ILCs.

J Exp Med 2017 Aug 11;214(8):2331-2347. Epub 2017 Jul 11.

Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

Innate lymphoid cells (ILCs) have been classified into "functional subsets" according to their transcription factor and cytokine profiles. Although cytokines, such as IL-12 and IL-23, have been shown to shape plasticity of ILCs, little is known about how the tissue microenvironment influences the plasticity, phenotype, and function of these cells. Here, we show clearly demarcated tissue specifications of -dependent ILCs across lymphoid and nonlymphoid organs. Although intestinal fate map-positive () ILCs show a clear ILC3 phenotype, lymphoid tissue-derived ILCs acquire an natural killer (NK) cell/ILC1-like phenotype. By adoptively transferring ILCs into recipient mice, we show that ILCs distribute among various organs and phenotypically adapt to the tissue environment they invade. When investigating their functional properties, we found that only lymphoid-tissue resident ILCs can suppress tumor growth, whereas intestinal ILC1s or NK cells fail to inhibit tumor progression. We thus propose that the tissue microenvironment, combined with ontogeny, provides the specific function, whereas the phenotype is insufficient to predict the functional properties of ILCs.
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http://dx.doi.org/10.1084/jem.20162031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551572PMC
August 2017

Interleukin-12 bypasses common gamma-chain signalling in emergency natural killer cell lymphopoiesis.

Nat Commun 2016 12 16;7:13708. Epub 2016 Dec 16.

Inflammation Research, Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland.

Differentiation and homeostasis of natural killer (NK) cells relies on common gamma-chain (γc)-dependent cytokines, in particular IL-15. Consequently, NK cells do not develop in mice with targeted γc deletion. Herein we identify an alternative pathway of NK-cell development driven by the proinflammatory cytokine IL-12, which can occur independently of γc-signalling. In response to viral infection or upon exogenous administration, IL-12 is sufficient to elicit the emergence of a population of CD122CD49b cells by targeting NK-cell precursors (NKPs) in the bone marrow (BM). We confirm the NK-cell identity of these cells by transcriptome-wide analyses and their ability to eliminate tumour cells. Rather than using the conventional pathway of NK-cell development, IL-12-driven CD122CD49b cells remain confined to a NK1.1NKp46 stage, but differentiate into NK1.1NKp46 cells in the presence of γc-cytokines. Our data reveal an IL-12-driven hard-wired pathway of emergency NK-cell lymphopoiesis bypassing steady-state γc-signalling.
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http://dx.doi.org/10.1038/ncomms13708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5172358PMC
December 2016

T cell contamination in flow cytometry gating approaches for analysis of innate lymphoid cells.

PLoS One 2014 23;9(4):e94196. Epub 2014 Apr 23.

Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.

Innate lymphoid cells (ILCs) differ from T and B cells as they do not express genetically rearranged antigen receptors. The most prominent member of this group, NK cells, can be identified by numerous surface receptors such as natural cytotoxicity receptors (NCRs). However, novel groups of ILCs have recently been described and classified based on fate-determining transcription factors and cytokines being produced, similarly to T helper cells. Due to the lack of exclusive markers, ILCs are primarily defined by the paucity of lineage markers. Using RORc-fate-mapping mice, we found that the common lineage exclusion using CD3 yields an ILC population containing a large proportion of T cells with recombined TCR loci and low expression of CD3. Thus, we suggest adding CD5 as a marker for thorough elimination of T cells to avoid erroneous interpretations of ILC function in immunity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0094196PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997334PMC
January 2015