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. 2018 Mar 6;9:440.
doi: 10.3389/fimmu.2018.00440. eCollection 2018.

Human Body Composition and Immunity: Visceral Adipose Tissue Produces IL-15 and Muscle Strength Inversely Correlates With NK Cell Function in Elderly Humans

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Free PMC article

Human Body Composition and Immunity: Visceral Adipose Tissue Produces IL-15 and Muscle Strength Inversely Correlates With NK Cell Function in Elderly Humans

Ahmad Al-Attar et al. Front Immunol. .
Free PMC article

Abstract

Natural killer (NK) lymphocyte-mediated cytotoxicity and cytokine secretion control infections and cancers, but these crucial activities decline with age. NK cell development, homeostasis, and function require IL-15 and its chaperone, IL-15 receptor alpha (IL-15Rα). Macrophages and dendritic cells (DC) are major sources of these proteins. We had previously postulated that additional IL-15 and IL-15Rα is made by skeletal muscle and adipose tissue. These sources may be important in aging, when IL-15-producing immune cells decline. NK cells circulate through adipose tissue, where they may be exposed to local IL-15. The objectives of this work were to determine (1) if human muscle, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) are sources of IL-15 and IL-15 Rα, and (2) whether any of these tissues correlate with NK cell activity in elderly humans. We first investigated IL-15 and IL-15Rα RNA expression in paired muscle and SAT biopsies from healthy human subjects. Both tissues expressed these transcripts, but IL-15Rα RNA levels were higher in SAT than in skeletal muscle. We also investigated tissue obtained from surgeries and found that SAT and VAT expressed equivalent amounts of IL-15 and IL-15Rα RNA, respectively. Furthermore, stromal vascular fraction cells expressed more IL-15 RNA than did adipocytes. To test if these findings related to circulating IL-15 protein and NK cell function, we tested 50 healthy adults aged > 70 years old. Plasma IL-15 levels significantly correlated with abdominal VAT mass in the entire cohort and in non-obese subjects. However, plasma IL-15 levels did not correlate with skeletal muscle cross-sectional area and correlated inversely with muscle strength. Plasma IL-15 did correlate with NK cell cytotoxic granule exocytosis and with CCL4 (MIP-1β) production in response to NKp46-crosslinking. Additionally, NK cell responses to K562 leukemia cells correlated inversely with muscle strength. With aging, immune function declines while infections, cancers, and deaths increase. We propose that VAT-derived IL-15 and IL-15Rα is a compensatory NK cell support mechanism in elderly humans.

Keywords: IL-15; adipose tissue; aging; natural killer cell; skeletal muscle strength.

Figures

Figure 1
Figure 1
IL-15 and IL-15Rα RNA levels in abdominal subcutaneous adipose tissue (SAT) normalized to values in paired vastus lateralis muscle samples in measured by RT-qPCR and normalized to four housekeeping genes in cohort A. Shown are means plus SEM. Each symbol for IL-15 and IL-15Rα represents an individual donor. IL-15 level did not significantly differ between tissues, but SAT expressed significantly more IL-15Rα RNA than did skeletal muscle (p = 0.012). Cohort A is described in Table S1 in Supplementary Material.
Figure 2
Figure 2
IL-15 and IL-15Rα RNA are produced in both subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). Except for one sample, all cohort B SAT samples were from females, from surgeries for panniculectomy (7), ventral hernia (1), breast reduction (4), and mastectomy (1). VAT subjects had surgeries for hernia repair (1), nephrectomy (3), colectomy (12), and gastrectomy (1). Cohort B is described in Table S1 in Supplementary Material.
Figure 3
Figure 3
IL-15 and IL-15Rα RNA are expressed in epiploic appendage (E), mesenteric (M), and omental (O) VAT. Cohort C subjects had surgeries for hernia repair (male #22, female #23, male #25), ostomy reversal (male #24), rectal intussusception (female #18), malfunctioning ileal conduit (male #19), large bowel obstruction (female #20), cancer (male #21, male #26, female #27, female #28), and acute appendicitis (male #29). Cohort C is described in Table S1 in Supplementary Material.
Figure 4
Figure 4
Subcutaneous adipose tissue (SAT) (A) and visceral adipose tissue (VAT) (B) stromal vascular fraction (SVF) cells produced more IL-15 RNA than did adipocytes (p = 0.012 and p = 0.043, respectively, by Wilcoxon Signed Rank Test) in cohort B. IL-15Rα RNA levels did not significantly differ between SVF and adipocytes. Adipocyte (A Adipo) and non-adipocyte (SVF Non-adipo) were calculated to exclude contaminating cells as described in Section “Materials and Methods.” All but one SAT samples were from female patients. SAT samples were from breast reductions (5), panniculectomy (4), and ventral hernia repair (1). None of the SAT cases involved cancer or other inflammatory diseases. VAT samples were from colectomies (5), exploratory laparotomy (1), and gastrectomy (1). Two VAT cases did not involve cancer. Cohort B is described in Table S1 in Supplementary Material.
Figure 5
Figure 5
Plasma IL-15 level associates with visceral adipose tissue (VAT) (A) and inversely associates with knee extensor peak torque (B) in cohort D. Associations of IL-15 with VAT were significant in all subjects (ρ = 0.442, p = 0.001) and in males (ρ = 0.657, p < 0.001), but not in females tested separately. IL-15 inversely associated with strength in all subjects (ρ = −0.348, p = 0.014) and in females (ρ = −0.581, p = 0.004), but not in males considered separately. Cohort D is described in Table S1 in Supplementary Material.
Figure 6
Figure 6
Strength (knee extensor peak torque) correlates inversely with measures of mature CD56dim natural killer (NK) cell responses to K562 leukemia cells in cohort D. CD56dim NK cell CD107a (A) is a measure of cytotoxic granule release and correlated inversely with peak torque for all subjects (ρ = −0.475, p = 0.001), but not for each sex considered individually. CD56dim NK cell MIP-1β chemokine production (B) correlated inversely with peak torque for all subjects (ρ = −0.384, p = 0.006), but not for each sex considered individually.
Figure 7
Figure 7
Observed associations (A) and proposed mechanistic relationships (B) between adipose tissue, IL-15, natural killer (NK) cells, and muscle. (A) Positive associations are represented by green arrows. Inverse associations are represented by red arrows. All arrows are double-headed, indicating that associations do not necessarily imply mechanism. Mechanistic model (B) is based on our findings and on published literature. Stimulatory mechanisms are represented by green arrows and inhibitory mechanisms are represented by the red arrow. Double-headed green arrows indicate mutually positive stimulation. We propose that adipose tissue is a significant source of IL-15, especially in aging humans. IL-15 stimulates NK cells. Importantly, IL-15 forms part of a positive feedback loop between adipose tissue NK cells, other type 1 innate lymphocytes, and macrophages, as represented by the double-headed green arrows. IL-15 and other inflammatory agents weaken muscle.

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References

    1. Spits H, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, et al. Innate lymphoid cells – a proposal for uniform nomenclature. Nat Rev Immunol (2013) 13:145–9.10.1038/nri3365 - DOI - PubMed
    1. Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, et al. Innate or adaptive immunity? The example of natural killer cells. Science (2011) 331:44–9.10.1126/science.1198687 - DOI - PMC - PubMed
    1. Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J, Miething C, et al. Senescence of activated stellate cells limits liver fibrosis. Cell (2008) 134:657–67.10.1016/j.cell.2008.06.049 - DOI - PMC - PubMed
    1. Pahl J, Cerwenka A. Tricking the balance: NK cells in anti-cancer immunity. Immunobiology (2015) 222(1):11–20.10.1016/j.imbio.2015.07.012 - DOI - PubMed
    1. Waldmann TA. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol (2006) 6:595–601.10.1038/nri1901 - DOI - PubMed

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