Adiponectin modulates NK‐cell function

Abstract

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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“…For example, earlier studies demonstrated that the adipocytokine adiponectin also influences NK cell function, although results were conflicting [16, 33, 34]. In addition, insulin-like growth factor 1 (IGF-1) was shown to modulate NK cell development and cytotoxicity [35].…”

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“…However, APN can also reportedly upregulate production of interferon γ by antigen-specific human CD4 and CD8 T cells in response to hepatitis C virus, thus possibly helping to control infection by this virus [44]. On the other hand, APN inhibits production of interferon γ by natural killer cells, although the effect on cytotoxicity is more subtle and may be activation-dependent [45, 46]. Increased levels of natural killer cell-derived interferon γ and reduced viral titers have been reported in APN KO mice infected with coxsackie virus compared to WT mice [46].…”

“…On the other hand, APN inhibits production of interferon γ by natural killer cells, although the effect on cytotoxicity is more subtle and may be activation-dependent [45, 46]. Increased levels of natural killer cell-derived interferon γ and reduced viral titers have been reported in APN KO mice infected with coxsackie virus compared to WT mice [46]. As these examples illustrate, the effect of APN in modulation of immune responses is likely highly context-dependent and needs to be further clarified.…”

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“…This persistence of "senescence" characterizing the cross-talk between white adipose tissue (WAT) and the liver does not facilitate the elimination/removal of the senescent cells; however, the p53-related promotion of adipose tissue adipogenesis with the development of NAFLD is allowed to take place. p53 is known to activate and suppress target genes like Sirt1, being associated with the innate immune response [70,71], as well as and SREBP-1 (sterol regulatory element-binding protein-1) [45,52], which serves as a key transcriptional regulator of the synthesis of lipids (triglycerides) in adipocytes. Sirt1, with its major role in lipid turnover in adipose tissue, is also metabolically "associated" to adiponectin release via the Sirt1/FOXO1 transcriptional complex [72,73], known to maintain basic hepatic functions.…”

“…Furthermore, the focus on α-synuclein and its impact on the immune system in the periphery [69,70] and CNS [71,72] have emerged as knowledge about its regulatory impact on p53 transcriptional regulation of apoptosis has increased. Sirt1-mediated effects on hepatic α-synuclein and amyloid-β turnover are closely linked to LPS [72], metabolic diseases, as well as obesity, with observed impact on p53 transcriptional regulation by both α-synuclein and amyloid-β metabolism in the liver and brain [73][74][75][76][77].…”