Abstract
Leptin is a cytokine, produced mainly by mature adipocytes, that regulates the central nervous system, mainly to suppress appetite and stimulate energy expenditure. Leptin also regulates the immune response by controlling activation of immunomodulatory cells, including eosinophils. While emerging as immune regulatory cells with roles in adipose tissue homeostasis, eosinophils have a well-established ability to synthesize pro-inflammatory molecules such as lipid mediators, a key event in several inflammatory pathologies. Here, we investigated the impact and mechanisms involved in leptin-driven activation of eicosanoid-synthesizing machinery within eosinophils. Direct in vitro activation of human or mouse eosinophils with leptin elicited synthesis of lipoxygenase as well as cyclooxygenase products. Displaying selectivity, leptin triggered synthesis of LTC4 and PGD2, but not PGE2, in parallel to dose-dependent induction of lipid body/lipid droplets biogenesis. While dependent on PI3K activation, leptin-driven eosinophil activation was also sensitive to pertussis toxin, indicating the involvement of G-protein coupled receptors on leptin effects. Leptin-induced lipid body-driven LTC4 synthesis appeared to be mediated through autocrine activation of G-coupled CCR3 receptors by eosinophil-derived CCL5, inasmuch as leptin was able to trigger rapid CCL5 secretion, and neutralizing anti-RANTES or anti-CCR3 antibodies blocked lipid body assembly and LTC4 synthesis induced by leptin. Remarkably, autocrine activation of PGD2 G-coupled receptors DP1 and DP2 also contributes to leptin-elicited lipid body-driven LTC4 synthesis by eosinophils in a PGD2-dependent fashion. Blockade of leptin-induced PGD2 autocrine/paracrine activity by a specific synthesis inhibitor or DP1 and DP2 receptor antagonists, inhibited both lipid body biogenesis and LTC4 synthesis induced by leptin stimulation within eosinophils. In addition, CCL5-driven CCR3 activation appears to precede PGD2 receptor activation within eosinophils, since neutralizing anti-CCL5 or anti-CCR3 antibodies inhibited leptin-induced PGD2 secretion, while it failed to alter PGD2-induced LTC4 synthesis. Altogether, sequential activation of CCR3 and then PGD2 receptors by autocrine ligands in response to leptin stimulation of eosinophils culminates with eosinophil activation, characterized here by assembly of lipidic cytoplasmic platforms synthesis and secretion of the pleiotropic lipid mediators, PGD2, and LTC4.
Highlights
Eosinophils are perceived as innate leukocytes with important roles in allergic conditions and parasitic infection
Human eosinophils upon stimulation preferentially synthesize leukotriene C4 (LTC4) as an arachidonic acid metabolite by activating the 5-LO pathway, it is well established that proper intracellular signaling within eosinophils can couple to COX-driven prostanoid synthesis [22]
Eosinophils are capable of PGE2 synthesis upon proper stimulation, such as with PAF–an eosinophil stimulus that triggers a different profile of eicosanoid synthesis by eosinophils with production of PGE2 (Figure 1A) and LTC4 (Figure 1C), but not prostaglandin D2 (PGD2) (Figure 1B) [28, 29]
Summary
Eosinophils are perceived as innate leukocytes with important roles in allergic conditions and parasitic infection. Eosinophils are recognized to be resident cells in different tissues where they play homeostatic roles, including uterine priming for pregnancy [4] or supporting mammary gland development [5, 6]. In healthy white adipose tissue, sentinel eosinophils preserve adipose homeostatic baseline and metabolic regulation, and mitigate obesity. In eosinophil-deficient mice, loss of adipose tissue eosinophil population allows phenotypic switch of macrophages from M2 to M1, setting up an inflammatory environment that culminates with weight gain and systemic insulin resistance [7]. Reduction of eosinophil numbers in obese adipose tissue reinforces the notion that eosinophil population is actively regulated across different physiological states of the adipose tissue [10, 11]
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