PMID- 29467755 OWN - NLM STAT- MEDLINE DCOM- 20190307 LR - 20190307 IS - 1664-3224 (Print) IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 9 DP - 2018 TI - Leptin Mediates In Vivo Neutrophil Migration: Involvement of Tumor Necrosis Factor-Alpha and CXCL1. PG - 111 LID - 10.3389/fimmu.2018.00111 [doi] LID - 111 AB - 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 B(4) (LTB(4)) 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 LTB(4) receptor antagonist (U-75302). Moreover, no direct induction of LTB(4) 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 (TNFalpha) 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 PI3Kgamma-dependent, as it was absent in PI3Kgamma(-/-) 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 TNFalpha/TNFR1- and CXCL1-dependent signaling as important pathways for leptin-induced neutrophil migration in vivo. FAU - Souza-Almeida, Glaucia AU - Souza-Almeida G AD - Laboratorio de Imunofarmacologia, Instituto Oswaldo Cruz, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil. FAU - D'Avila, Heloisa AU - D'Avila H AD - Instituto de Ciencias Biologicas, Universidade Federal de Juiz de Fora, Juiz de Fora, Brazil. FAU - Almeida, Patricia E AU - Almeida PE AD - Instituto de Ciencias Biologicas, Universidade Federal de Juiz de Fora, Juiz de Fora, Brazil. FAU - Luna-Gomes, Tatiana AU - Luna-Gomes T AD - Instituto de Ciencias Biologicas, Universidade Federal de Juiz de Fora, Juiz de Fora, Brazil. AD - Departamento de Ciencias da Natureza, Instituto de Aplicacao Fernando Rodrigues da Silveira, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Liechocki, Sally AU - Liechocki S AD - Laboratorio de Imunofarmacologia, Instituto Oswaldo Cruz, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil. FAU - Walzog, Barbara AU - Walzog B AD - Walter Brendel Centre of Experimental Medicine, Department of Cardiovascular Physiology and Pathophysiology, Biomedical Center, Ludwig-Maximilians-Universitat Munchen, Munich, Germany. FAU - Hepper, Ingrid AU - Hepper I AD - Walter Brendel Centre of Experimental Medicine, Department of Cardiovascular Physiology and Pathophysiology, Biomedical Center, Ludwig-Maximilians-Universitat Munchen, Munich, Germany. FAU - Castro-Faria-Neto, Hugo Caire AU - Castro-Faria-Neto HC AD - Laboratorio de Imunofarmacologia, Instituto Oswaldo Cruz, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil. FAU - Bozza, Patricia T AU - Bozza PT AD - Laboratorio de Imunofarmacologia, Instituto Oswaldo Cruz, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil. FAU - Bandeira-Melo, Christianne AU - Bandeira-Melo C AD - Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Maya-Monteiro, Clarissa M AU - Maya-Monteiro CM AD - Laboratorio de Imunofarmacologia, Instituto Oswaldo Cruz, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil. LA - eng GR - HHMI/Howard Hughes Medical Institute/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180206 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Ccl3 protein, mouse) RN - 0 (Chemokine CCL3) RN - 0 (Chemokine CXCL1) RN - 0 (Cxcl1 protein, mouse) RN - 0 (Leptin) RN - 0 (Receptors, Tumor Necrosis Factor, Type I) RN - 0 (Tnfrsf1a protein, mouse) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 1.13.11.34 (Arachidonate 5-Lipoxygenase) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) SB - IM MH - Animals MH - Arachidonate 5-Lipoxygenase/genetics MH - Cell Movement MH - Chemokine CCL3/genetics MH - Chemokine CXCL1/*physiology MH - Leptin/*physiology MH - Macrophages, Peritoneal/immunology MH - Male MH - Mice, Inbred C3H MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Neutrophil Infiltration MH - Neutrophils/*physiology MH - Phosphatidylinositol 3-Kinases/genetics MH - Receptors, Tumor Necrosis Factor, Type I/*physiology MH - Tumor Necrosis Factor-alpha/*physiology PMC - PMC5808117 OTO - NOTNLM OT - CXCL1 OT - inflammation OT - leptin OT - leukotriene B4 OT - neutrophil OT - tumor necrosis factor-alpha EDAT- 2018/02/23 06:00 MHDA- 2018/02/23 06:01 PMCR- 2018/01/01 CRDT- 2018/02/23 06:00 PHST- 2017/10/06 00:00 [received] PHST- 2018/01/15 00:00 [accepted] PHST- 2018/02/23 06:00 [entrez] PHST- 2018/02/23 06:00 [pubmed] PHST- 2018/02/23 06:01 [medline] PHST- 2018/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2018.00111 [doi] PST - epublish SO - Front Immunol. 2018 Feb 6;9:111. doi: 10.3389/fimmu.2018.00111. eCollection 2018.