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

Glaucia Souza-Almeida,Christianne Bandeira-Melo,Clarissa M Maya-Monteiro,Ingrid Hepper,Patricia T Bozza,Heloisa D’Avila,Hugo Caire Castro-Faria-Neto,Barbara Walzog,Patricia E Almeida,Sally Liechocki,Tatiana Luna-Gomes

doi:10.3389/fimmu.2018.00111

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.

Highlights

A growing body of evidence indicates that leptin is a key modulator of the homeostasis of the immune system [1, 2]
Leptin deficiency is associated with impaired cell-mediated immunity and increased susceptibility to infection [1], and neutrophil chemotaxis is a key component of inflammation and host response to infection
We demonstrated here that the in vivo administration of leptin significantly induces neutrophil recruitment to the peritoneal cavity

Summary

INTRODUCTION

A growing body of evidence indicates that leptin is a key modulator of the homeostasis of the immune system [1, 2]. The mechanism of leptin-induced leukocyte activation and recruitment in vivo needs further investigation. Leptin indirectly induces the in vitro neutrophil expression of CD11b in response to the direct stimulation of macrophages [10]. Leptin is known to be important for a proper response to infections and immunological homeostasis, but little is known about the in vivo modulation of neutrophil migration by leptin [12]. We decided to investigate how leptin can activate and induce inflammatory mediators indirectly causing neutrophil migration in vivo, with potential implications for a number of inflammatory conditions in different diseases. We show that exogenous leptin induces in vivo migration and persistent neutrophil accumulation in the peritoneal cavity, through a mechanism largely dependent on TNFα and CXCL1 but independent of LTB4 production and signaling

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ETHICS STATEMENT