Natural Killer Cells in Obesity: Impaired Function and Increased Susceptibility to the Effects of Cigarette Smoke

O’Shea, Donal; Cawood, Tom; O’Farrelly, Cliona; Lynch, Lydia

doi:10.1371/journal.pone.0008660

Cited by 143 publications

(152 citation statements)

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Section: Discussionsupporting

confidence: 94%

“…In contrast, human NK-cell degranulation and cytotoxicity were not influenced by APN. Our finding is in accordance with a more recent study in humans in which APN did not inhibit NK-cell cytotoxicity and even partially restored the inhibitory effect of cigarette smoke [17].A production in murine NK cells. We identified a major difference between human and murine NK-cell surface AdipoR expression, which we observed only on a minor subset of resting murine NK cells.…”

supporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

“…Few instances of largely conflicting data have been published regarding the regulation of NK-cell function and generation by APN. In one study APN was shown to suppress IL-2-induced NK-cell cytotoxicity in mice [16], whereas O'Shea et al [17] described APN as an inducer of cytotoxicity in lean human subjects.In the present study the expression of AdipoRs and the role of APN in NK-cell function in humans and mice were analyzed. Furthermore, the role of APN on NK-cell function during viral infection was assessed by comparing NK-cell function in WT and adiponectin knockout (APN-KO) mice upon CVB3 infection.…”

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confidence: 99%

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Adiponectin modulates NK‐cell function

et al. 2013

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Adiponectin (APN) has been shown to exert antiinflammatory effects in various disease models but little is known concerning its regulation of NK-cell function. Here, weshow that the majority of human CD56 dim NK cells express surface Adiponectin receptor (AdipoR) 1 and 2 while most CD56 high NK cells are AdipoR-negative. Toll-like receptor (TLR) ligand-induced IFN-γ production was diminished by APN while it had no influence on NK-cell cytotoxicity. In contrast only a small subpopulation of murine NK cells expresses surface AdipoRs, but about 90% store them intracellularly. APN-deficient knockout (KO) mice had elevated frequencies of NK cells. However, cytotoxic degranulation of NK cells was decreased in APN knockout (APN-KO) animals. Accordingly, frequencies of CD11b high CD27 high and CD94 high effector NK cells and expression of NKG2D were lower in APN-KO mice. Upon CVB3 infection NK-cell function was restored in APN-KO mice. Our data suggest that in addition to its antiinflammatory effects APN also influences the numerical and differentiation status of NK cells, which may further impact the outcome of immune-mediated diseases in APN-KO mice.Keywords: Adiponectin r Adiponectin KO mice r Adiponectin receptors 1 or 2 r Immunomodulation r NK cells Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAdiponectin (APN), a cytokine, accounting for 0.01% of total plasma protein, is mainly produced by adipocytes under steadystate conditions and negatively regulated by obesity [1,2]. Adiponectin has been shown to exert antiinflammatory effects in several disease models such as sepsis, inflammatory diseases, and Correspondence: Prof. Carmen Scheibenbogen e-mail: Carmen.Scheibenbogen@charite.de transplantation. In accordance, APN-deficient mice are more prone to transplant rejection and inflammatory diseases [3][4][5].APN signaling is mediated by two receptors, adiponectin receptor (AdipoR) 1 and 2, with different affinities for existing isoforms. AdipoR1 is ubiquitous, but most prominent in skeletal muscle and heart, whereas AdipoR2 is abundantly expressed in the liver [6]. AdipoRs expression was further described in cells of the immune system [7,8]. Several studies revealed the direct action of APN on cells of the innate and adaptive immune system [1,9]. APN was shown to inhibit TLR-mediated NF-κB activation in macrophageswww.eji-journal.eu Eur. J. Immunol. 2013. 43: 1024-1033 Immunomodulation 1025[10] and to induce macrophage polarization toward the antiinflammatory M2 phenotype [11]. In a recent study we could further demonstrate that T cells store AdipoRs intracellularly, upregulate them upon T-cell receptor activation, and that APN acts as a negative T-cell regulator for antigen-activated T cells [8]. Furthermore, APN has been described as a negative regulator of hematopoiesis inhibiting directly proliferation of myelomonocytic progenitors [12] or indirectly through inducing changes in stromal cells [13]. NK cells are innate effector lymphocyte...

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Section: Discussionsupporting

confidence: 94%

supporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Adiponectin modulates NK‐cell function

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“…There are well-described effects of obesity on the circulating and adipose tissue (AT)-based immune system. The net result is sterile inflammation, which appears to underpin many of the conditions that obesity causes (4)(5)(6)(7)(8).…”

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confidence: 99%

Altered Distribution and Increased IL-17 Production by Mucosal-Associated Invariant T Cells in Adult and Childhood Obesity

Carolan

Tobin

Mangan

et al. 2015

The Journal of Immunology

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Mucosal-associated invariant T (MAIT) cells are innate MHC-unrestricted cells that regulate inflammatory responses through the rapid production of cytokines. In this article, we show that circulating MAIT cells are depleted in obese adults, and depletion is associated with diabetic status. Circulating MAIT cells more frequently produced IL-17 upon stimulation ex vivo, a cytokine implicated in insulin resistance. MAIT cells were enriched in adipose tissue (AT) compared with blood. AT MAIT cells, but not circulating MAIT cells, were capable of producing IL-10. In AT from obese subjects, MAIT cells were depleted, were less likely to produce IL-10, and more frequently produced IL-17. Finally, we show that IL-17+ MAIT cells are also increased in childhood obesity, and altered MAIT cell frequencies in obese children are positively associated with insulin resistance. These data indicate that MAIT cells are enriched in human AT and display an IL-17+ phenotype in both obese adults and children, correlating with levels of insulin resistance. The alterations in MAIT cells may be contributing to obesity-related sterile inflammation and insulin resistance.

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