Significantly enhanced lung metastasis and reduced organ NK cell functions in diet-induced obese rats

Spielmann, Julia; Hanke, J; Knauf, Daniel G.; Ben‐Eliyahu, Shamgar; Jacobs, Roland; Stangl, Gabriele I.; Bähr, Ina; Kielstein, Heike

doi:10.1186/s40608-017-0161-5

Cited by 15 publications

(20 citation statements)

References 49 publications

(49 reference statements)

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“…Animal studies on diet-induced rats injected with a metastatic breast cancer cell line reported a reduced NK cell number in the blood as well as a decrease of NK cell-tumor cell interactions in the lung, compared to lean animals. Furthermore, obese rats showed reduced NKG2D expression levels in the spleen combined with an enhanced number of lung metastasis (143). Accordingly, obese mice injected with breast cancer cells revealed a lower NK cell number in blood and spleen as well as a reduced NK cell cytotoxicity against lymphoma cells, compared to their lean littermates (140).…”

Section: The Impact Of Obesity-related Altered Nk Cell Functionality mentioning

confidence: 95%

“…However, in addition to changes in NK cell number, the expression of the activating NK cell receptors NKp46 and NKG2D in splenic tissue and NKp30 in liver tissue was reduced in diet-induced obese rats, indicating an inhibited activation status of NK cells in obesity (93,143). Moreover, NK cells of obese rodents exhibit a reduced cytotoxicity against tumor cells compared to NK cells isolated from normal weight animals (13,131,140,144).…”

Section: The Impact Of Systemic Obesity On Nk Cells In Animal Studiesmentioning

confidence: 99%

“…Data exist about differences in NK cell numbers in peripheral blood and organs, although the results are conflicting. Numerous studies demonstrated a decrease of the NK cell amount in blood as well as in spleen, lung, and liver of obese rodents (93,98,131,(140)(141)(142)(143). In contrast, other reports exist showing either no changes or an increase of the NK cell number in blood and different tissues of obese individuals (75,93,97,131,132,136,138,142).…”

Section: The Impact Of Systemic Obesity On Nk Cells In Animal Studiesmentioning

confidence: 99%

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Obesity-Associated Alterations of Natural Killer Cells and Immunosurveillance of Cancer

et al. 2020

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Obesity is accompanied by a systemic chronic low-grade inflammation as well as dysfunctions of several innate and adaptive immune cells. Recent findings emphasize an impaired functionality and phenotype of natural killer (NK) cells under obese conditions. This review provides a detailed overview on research related to overweight and obesity with a particular focus on NK cells. We discuss obesity-associated alterations in subsets, distribution, phenotype, cytotoxicity, cytokine secretion, and signaling cascades of NK cells investigated in vitro as well as in animal and human studies. In addition, we provide recent insights into the effects of physical activity and obesity-associated nutritional factors as well as the reduction of body weight and fat mass on NK cell functions of obese individuals. Finally, we highlight the impact of impaired NK cell physiology on obesity-associated diseases, focusing on the elevated susceptibility for viral infections and increased risk for cancer development and impaired treatment response.NK cells are large granular lymphocytes that mediate rapid innate immunity against viruses, bacteria, parasites, and tumor cells without prior sensitization. NK cells primarily develop and mature in the bone marrow, migrate through the bloodstream, and seed into secondary lymphoid organs, like thymus, spleen, and lymph nodes as well as in other peripheral tissues, like lung, liver, kidney, uterus, and the gastrointestinal tract (23). In blood, NK cells represent 1-6% of all leukocytes and comprise up to 15% of human peripheral blood mononuclear cells (PBMCs). Human NK cells have been defined by the expression of adhesion molecule CD56 and by the absence of the T cell marker CD3. Based on their expression level of CD56 and the Fcγ receptor CD16, NK cells are subdivided into different subpopulations. The two major and classically defined subsets are the CD56 dim CD16 bright NK cells and the CD56 bright CD16 dim/neg NK cells. CD56 dim CD16 bright NK cells represent about 90% of all NK cells and are predominantly found in peripheral blood (24). They are mostly responsible for cytotoxic activity and target cell killing but are also a source of pro-inflammatory Abbreviations: ACM, adipocyte-conditioned media; Adamts3, a disintegrin-like and metallopeptidase with thrombospondin type 1 motif, 3; AdipoR, adiponectin receptor; Anxa8, annexin A8; AT, adipose tissue; Bax, Bcl-2-associated X protein; Bcl, B-cell lymphoma; BMI, body mass index; CCR, CC chemokine receptor; Csf1r, colony stimulating factor 1 receptor; CX3CR1, C-X3-C-motif chemokine receptor 1; DNAM-1, DNAX accessory molecule-1; ESR, estrogen receptor; FasL, Fas ligand; IFN-γ, interferon; GM-CSF; granulocyte macrophage colony-stimulating factor; H6pd, hexose-6-phosphate dehydrogenase; Hk2, hexokinase 2; IL, interleukinIL-6R; interleukin-6 receptor; Il18rap, interleukin 18 receptor accessory protein; IP-10, interferon gamma-induced protein 10; JAK, Janus kinase; KIR, killer immunoglobulin-like receptor; Klra1, killer lectin-like receptor subfamil...

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Section: The Impact Of Obesity-related Altered Nk Cell Functionality mentioning

confidence: 95%

Section: The Impact Of Systemic Obesity On Nk Cells In Animal Studiesmentioning

confidence: 99%

Section: The Impact Of Systemic Obesity On Nk Cells In Animal Studiesmentioning

confidence: 99%

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Obesity-Associated Alterations of Natural Killer Cells and Immunosurveillance of Cancer

et al. 2020

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“…In a rodent lung metastasis model Spielmann et al could demonstrate significantly increased lung metastasis in dietinduced obese rats accompanied with decreased numbers of NK cells in the lung tissue, reduced NK cell-tumor cell contacts and reduced expression of the activating NK cell receptor NKG2D. 41 …”

Section: Discussionmentioning

confidence: 99%

Leptin affects filopodia and cofilin in NK-92 cells in a dose- and time-dependent manner

et al. 2018

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Hyperleptinemia, associated with obesity, is related with immune dysfunction and carcinogenesis. Natural Killer (NK) cells, a major component of the innate immune system are mediators of anti-tumor immunity and the most actively migrating cells among leukocytes. Actin rearrangement, promoted by cofilin plays a central role in cellular migration. Leptin affects the phosphorylation- dependent activity of cofilin and thus actin remodeling. We used human NK-92 cells to explore the in vitro effects of leptin on co-localization of cofilin and F-actin and on morphological changes in NK cells. NK- 92 cells were incubated with different leptin concentrations (10 and 100 ng/mL) for 30 min and 24 h and immunocytochemically stained. Results demonstrate a dose- and time-dependent influence of leptin on cellular morphology. Utilizing confocal microscopy, we observed that the co-localization of cofilin-1 and F-actin was slightly influenced by leptin. In summary, the present study demonstrates an impact of a physiological leptin stimulation on the filopodia length, and a time-dependent effect on the co-localization of cofilin and F-actin in NK- 92 cells.

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“…Wertvolle Erkenntnisse liefert in dieser Studie auch ein Versuch an Ratten, der zeigen konnte, dass es bei Diät-induziert adipösen Tiere nach chemischer Induktion eines Kolonkarzinoms zu einer verminderten Expression der aktivierenden NK-Zellrezeptoren NKp46 und NKG 2D und folglich zur Ausbildung von zahlreicheren, größeren und schwereren Tumoren im Kolon kam. Bestätigt wurden diese Beobachtungen durch einen Versuch, in welchem Diät-induziert adipöse Ratten nach Injektion der Brustkrebszelllinie MADB106 eine signifikant verringerte Anzahl an NK-Zellen und NK-Zell-Tumorzellkontakten in der Lunge im Vergleich zu den normalgewichtigen Tieren aufwiesen [49]. In der Folge konnte hier ebenfalls eine verminderte Genexpression des aktivierenden NK-Zell-Rezeptors NKG 2D und drei Wochen nach Injektion der Tumorzellen auch signifikant mehr Lungenmetastasen in den adipösen Tieren gefunden werden ▶Abb.…”

Section: Killer Gegen Krebsunclassified

Natürliche Killerzellen, Adipositas & Tumorgenese

Spielmann¹,

Bähr²,

Naujoks³

et al. 2019

Adipositas - Ursachen, Folgeerkrankungen, Therapie

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ZusammenfassungDie Prävalenz für Adipositas nimmt sowohl in Industrienationen als auch in Entwicklungsländern stetig zu. So hat sich die Zahl der fettleibigen Menschen in den vergangenen 30 Jahren nahezu verdoppelt. Nach Schätzungen der WHO sind weltweit 1,5 Milliarden Menschen übergewichtig (BMI ≥ 25 kg/m²); 500 Millionen Menschen gelten bereits als adipös (BMI ≥ 30 kg/m²). In Deutschland sind entsprechend den Angaben des Robert-Koch-Institutes 67,1 % der Männer und 53,0 % der Frauen übergewichtig; rund 23 % aller Erwachsenen sind adipös. Neben Adipositas-assoziierten Folge- oder Begleiterkrankungen, wie Diabetes mellitus Typ 2, kardiovaskuläre und degenerative Erkrankungen und Fettstoffwechselstörungen ist auch die Prävalenz für die Entstehung von Karzinomen durch Adipositas erhöht. Insbesondere häufig auftretende Krebsarten wie postmenopausaler Brustkrebs und Darmkrebs stellen ein enormes medizinisches, soziales und gesundheitspolitisches Problem dar. Das veränderte metabolisch-immunologische Gleichgewicht, infolge von Übergewicht und Adipositas, führt zu Funktionsverlusten von Immunzellen des angeborenen und erworbenen Immunsystems, einschließlich den Natürlichen Killerzellen (NK-Zellen) als Vertreter der angeborenen Immunität. Das heutige Wissen über die Funktionsveränderungen von NK-Zellen im adipösen Organismus und deren Konsequenz für die Entstehung und Pathogenese von Tumoren wird in dieser Übersichtsarbeit dargestellt. Präklinische Interventionen mit beeindruckenden zellbiologischen Effekten werden diskutiert.

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Significantly enhanced lung metastasis and reduced organ NK cell functions in diet-induced obese rats

Cited by 15 publications

References 49 publications

Obesity-Associated Alterations of Natural Killer Cells and Immunosurveillance of Cancer

Obesity-Associated Alterations of Natural Killer Cells and Immunosurveillance of Cancer

Leptin affects filopodia and cofilin in NK-92 cells in a dose- and time-dependent manner

Natürliche Killerzellen, Adipositas & Tumorgenese

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