Leptin Mediates In Vivo Neutrophil Migration: Involvement of Tumor Necrosis Factor-Alpha and CXCL1

Abstract

Leptin directly activates macrophages and lymphocytes, but the role of leptin in neutrophil activation and migration is still controversial. Here, we investigate the in vivo mechanisms of neutrophil migration induced by leptin. The intraperitoneal injection of leptin (1 mg/kg) induces a time- and concentration-dependent neutrophil influx. We did not observe the enhancement of lipid bodies/droplets in neutrophils, after leptin treatment, as we had observed previously in peritoneal macrophages. The participation of leukotriene B4 (LTB4) in neutrophil recruitment triggered by leptin was investigated using different strategies. Leptin-induced neutrophil recruitment occurs both in the absence of 5-lipoxygenase activity in 5-lipoxygenase (5-LO)−/− mice and after the administration of either 5-LO inhibitor (Zileuton) or the LTB4 receptor antagonist (U-75302). Moreover, no direct induction of LTB4 by leptin could be observed. Neutrophil influx could not be prevented by the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, contrasting with the leptin-induced signaling for lipid body formation in macrophage that is mTOR-dependent. Leptin administration led to tumor necrosis factor-alpha (TNFα) production by the peritoneal cells both in vivo and in vitro. In addition, neutrophil recruitment was inhibited in tumor necrosis factor receptor 1 (TNFR1−/−) mice, indicating a role for TNF in leptin-induced neutrophil recruitment to the peritoneal cavity. Leptin-induced neutrophil influx was PI3Kγ-dependent, as it was absent in PI3Kγ−/− mice. Accordingly, leptin induced the peritoneal cells to produce CXCL1, both in vivo and in vitro, and the neutrophil influx was ablated after using an antibody against CXCL1. Our results establish TNFα/TNFR1- and CXCL1-dependent signaling as important pathways for leptin-induced neutrophil migration in vivo.

Short‐term high‐fat diet feeding protects from the development of experimental allergic asthma in mice

“…Alternatively, obesity, in acute lung injury, suppresses neutrophil chemotaxis through the downregulation of chemotactic receptors such as CXCR2. 45 Also, leptin acts either as a neutrophil chemoattractant, directly or through the release of TNF-α and CXCL1 by peritoneal cells, 46 or as a suppressor of C5a-or FMLP-induced chemoattraction. 47 Short-term HFD-fed mice in our model display dyslipidaemia.…”

Leptin in the regulation of the immunometabolism of adipose tissue-macrophages

“…Besides, it is known that leptin activates immune cells and induces the production of TNF‐α, a known lipolytic factor, which favors a proinflammatory and prolipolytic milieu in the WAT (Fig. ) . Importantly, TNF‐α together with other adipokines and cytokines from resident and recruited immune cells compose the adipose tissue microenvironment, which can modulate adipogenesis and proliferation of adipocyte precursor cells .…”

“…93,95 However, in these cases, it is difficult to assume a direct effect of leptin on adipocytes because, as aforementioned, WAT is composed of a variety of cell types with M s making up for up to 50% of the total cell number in adipose tissue during obesity. 96,97 Besides, it is known that leptin activates immune cells and induces the production of TNF-, 98 a known lipolytic factor, [99][100][101][102] which favors a proinflammatory and prolipolytic milieu in the WAT (Fig. 2).…”

“…2). [98][99][100][101][102] Importantly, TNFtogether with other adipokines and cytokines from resident and recruited immune cells compose the adipose tissue microenvironment, which can modulate adipogenesis and proliferation of adipocyte precursor cells. 103 In another study, adipocytes were isolated from rat subcutaneous, epididymal, and perirenal adipose tissue and then stimulated with leptin for 2 h. 94 The authors concluded that leptin induced lipolysis in cells from these 3 fat depots by measuring the levels of secreted glycerol, a metabolite from the breakdown of stored triacylglycerol.…”

Leptin Induces Proadipogenic and Proinflammatory Signaling in Adipocytes

“…We have previously shown that leptin can induce formation of lipid droplets in an mTOR-dependent manner, in different cell types (13)(14)(15). In peripheral tissues, leptin participates in reproduction (16), activation of immune cells (15,17,18), cell proliferation (14), osteogenesis (19), among many other functions. Leptin levels are increased during obesity but leptin signaling in the hypothalamus is impaired, a phenomenon called central leptin resistance (9,20,21).…”