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Leptin As a Uremic Toxin Interferes with Neutrophil Chemotaxis

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Leptin As a Uremic Toxin Interferes with Neutrophil Chemotaxis J Am Soc Nephrol 15: 2366–2372, 2004 Leptin as a Uremic Toxin Interferes with Neutrophil Chemotaxis LUCIANO OTTONELLO,* PAOLA GNERRE,* MARIA BERTOLOTTO,* MARINA MANCINI,* PATRIZIA DAPINO,* RODOLFO RUSSO,† GIACOMO GARIBOTTO,† TOMMASO BARRECA,* and FRANCO DALLEGRI* *Division of Internal Medicine and †Division of Nephrology, Department of Internal Medicine and Medical Specialties, University of Genoa Medical School, Genoa, Italy Abstract. Leptin is a pleiotropic molecule involved in energy Finally, the serum inhibitory activity can be effectively prevented homeostasis, hematopoiesis, inflammation, and immunity. Hypo- by immune depletion of leptin. The results also show, however, leptinemia characterizing starvation has been strictly related to that leptin by itself is endowed with chemotactic activity toward increased susceptibility to infection secondary to malnutrition. neutrophils. The two activities—inhibition of the cell response to Nevertheless, ESRD is characterized by high susceptibility to chemokines and stimulation of neutrophil migration—could be bacterial infection despite hyperleptinemia. Defects in neutrophils detected at similar concentrations. On the contrary, neutrophils 2ϩ play a crucial role in the infectious morbidity, and several uremic exposed to leptin did not display detectable [Ca ]i mobilization, ␤ toxins that are capable of depressing neutrophil functions have oxidant production, or 2-integrin upregulation. The results dem- been identified. Only a few and contrasting reports about leptin onstrate that leptin is a pure chemoattractant devoid of secreta- and neutrophils are available. This study provides evidence that gogue properties that are capable of inhibiting neutrophil chemo- leptin inhibits neutrophil migration in response to classical che- taxis to classical neutrophilic chemoattractants. Taking into moattractants. Moreover, serum from patients with ESRD inhibits account the crucial role of neutrophils in host defense, the leptin- migration of normal neutrophils in response to N-formyl-methio- mediated ability of ERSD serum to inhibit neutrophil chemotaxis nyl-leucyl-phenylalanine with a strict correlation between serum appears as a potential mechanism that contributes to the establish- leptin levels and serum ability to suppress neutrophil locomotion. ment of infections in ERSD. The obese (ob) gene (1) product, named leptin from the Greek by human monocytes (14) as well as the production of TNF term leptos, meaning thin, is a 16-kD nonglycosylated peptide and IL-6 (15). Recent findings show that leptin positively hormone involved in the control of food intake (2). It is modulates mononuclear cell survival by interfering with the predominantly synthesized by adipocytes (3) to limit the intake apoptotic process (16). More striking, hypoleptinemia charac- of food, promote the breakdown of fat, and increase energy terizing starvation is strictly related to increased susceptibility expenditure (4,5). Indeed, spontaneous mutations in leptin or to infection secondary to malnutrition (12,17). Thus, leptin can its receptor result in marked obesity (6,7). Evidence is accu- be considered part of the recently categorized family of mol- mulating that leptin also plays a role in innate and acquired ecules produced by adipose tissue called adipokines, which are immunity (8,9). In fact, leptin and its receptor share structural capable of linking metabolism and immune homeostasis similarities with members of the long-chain helical cytokine (17,18). Adipokines include cytokines such as IL-1, IL-6, family, which includes IL-6, IL-11, and IL-12 (10,11). Con- IFN-␥, and TNF-␣ and chemokines such as IL-8, monocyte sistent with this view, leptin regulates T lymphocyte responses, chemotactic protein-1 (MCP-1), and macrophage inflamma- and, in particular, it polarizes T helper (Th) cells toward a Th1 tory protein-1␣ (MIP-1␣) (17). phenotype by enhancing proliferation and IL-2 production of Nevertheless, there are some remarkable exceptions to this naive T cells (12). Furthermore, leptin increases the secretion paradigm: In particular, ESRD is characterized by high sus- of TNF-␣, IL-6, and IL-12 by endotoxin-stimulated murine ceptibility to bacterial infection (19) despite high levels of peritoneal macrophages (13). In addition, leptin induces the leptinemia (20,21). In agreement with this observation, another expression and secretion of IL-1 receptor antagonist (IL-1Ra) hyperleptinemic condition, obesity (22), is also associated with an increased incidence of infections (23). As far as ESRD is concerned, it is generally assumed that the defects in phago- Received April 20, 2004. Accepted June 28, 2004. cytic polymorphonuclear neutrophilic leukocytes (neutrophils) Correspondence to Dr. Luciano Ottonello, Dipartimento di Medicina Interna e Specialità Mediche, Viale Benedetto XV n. 6, I-16132 Genova, Italy. Phone: plays a crucial role in the infectious morbidity (24), and, ϩ39-010-3538686; Fax: ϩ39-010-3538686; E-mail: [email protected] indeed, several uremic toxins (e.g., molecules that are capable 1046-6673/1510-2366 of depressing neutrophil functions) have been identified Journal of the American Society of Nephrology (25,26). Despite active investigations regarding other immune Copyright © 2004 by the American Society of Nephrology cells, only a few reports about leptin and neutrophils are DOI: 10.1097/01.ASN.0000139321.98029.40 available. Furthermore, these works originated contrasting data J Am Soc Nephrol 15: 2366–2372, 2004 Neutrophil Chemotaxis Inhibition by Leptin 2367 about the capacity of leptin of modulating neutrophil activities. g, 45 min) and immediately tested in the chemotactic assays and in In particular, two papers from the group of Caldefie-Chezet leptin assays. (27,28) show that leptin is capable of triggering the oxidative and locomotory capacities of neutrophils without affecting Neutrophil Preparation phagocytosis. Conversely, Zarkesh-Esfahani et al. (29) did not Heparinized venous blood (10 U/ml heparin) was obtained from observe any direct effect of leptin on neutrophil activation. The healthy male volunteers after informed consent. Neutrophils were aim of the present work was to study the actual capability of isolated by dextran sedimentation and subsequent centrifugation on leptin to modulate neutrophil functional activities and, in case a Ficoll-Hypaque density gradient, as described previously (30). of positive results, to investigate a possible role of this hor- Contaminating erythrocytes were removed by hypotonic lysis (30). Then, neutrophils were washed three times with HBSS and resus- mone in the pathogenesis of neutrophil dysfunctions charac- pended in incubation medium at appropriate concentrations. Final terizing ESRD. cell suspension was Ͼ97% pure and Ͼ98% viable, as determined by usual assays (30). Materials and Methods Culture Medium and Reagents Neutrophil Locomotion Hanks’ balanced salt solution (HBSS; EuroCLone, Wetherby West, Neutrophil locomotion was studied using the leading front method, Yorkshire, UK) mixed with Dulbecco’s PBS (EuroClone; HBBS:PBS as described previously (30). Tests were conducted in duplicate using ␮ ϭ 3:1) containing 1 mg/ml BSA (Sigma Chemical Co., St. Louis, blind well chambers (NeuroProbe, Cabin John, MA) with a 3- m pore MO) was used as incubation medium throughout the study. Ficoll- size cellulose ester filter (Millipore, Milan, Italy) separating the cells ϫ 5 Hypaque (Lympholyte-I), Giemsa stain, and heparin were purchased (4 10 ) from the chemoattractant. After incubation at 37°C for 45 from Cedarlane Laboratories Ltd. (Hornby, Ontario, Canada), Merck min, the filters were removed, fixed in ethanol, stained with Harris (Darmstadt, Germany), and Roche (Milan, Italy), respectively. Fluo- hematoxylin, dehydrated, cleared with xylene, and mounted in Eukitt rescein diacetate, HEPES, N-formyl-methionyl-leucyl-phenylalanine (Kindler, GmbH, Freiburg, Germany). Duplicate chambers were run ␮ (FMLP), human recombinant C5a, and human recombinant leptin in each case, and the distance ( m) traveled by the leading front of ϫ were purchased from Sigma. FITC-conjugated anti-CD11b mAb 44 cells was measured at 400 magnifications; five randomly chosen (IgG1) and recombinant human IL-8 were purchased from Biosource fields were read for each filters. International (Camarillo, CA). Mouse anti-human leptin 44802 mAb 2ϩ was from R&D System Europe (Abingdon, UK). Fura-2 AM and Intracellular [Ca ]i Determination 2',7'-dichlorofluorescin-diacetate (DCFH-DA) were from Molecular Neutrophils (2.5 ϫ 106) were loaded with 2 ␮M fura-2 AM in Probes (Eugene, OR). Endotoxin contamination of the reagents used HBSS-HEPES 10 mM (pH 7.4; 30 min, 37°C, final volume 0.5 ml). was tested by manufacturers or directly by QLC-1000 Assay (Cam- Then, cell suspension was diluted 10-fold with HBSS-HEPES, incu- brex Bio Science Walkersville, Inc., Walkersville, MD). bated for 30 min at 37C°, washed twice, and resuspended in HBSS- HEPES. Fluorescence changes before and after addition of leptin or FMLP were monitored with Perkin-Elmer LS3 spectrofluorometer at Patients an excitation wavelength of 338 nm and an emission wavelength of The study population consisted of 18 patients with ESRD (7 men 510 nm (30). and 11 women; mean age, 62.3 Ϯ 17.8, x Ϯ 1 SD) under hemodialytic ϭ ϭ (n 13) or peritoneal dialytic (n 5) treatment. All were outpatients, Superoxide Anion Release Assay and the diagnoses were as follows: chronic glomerulonephritis (n ϭ The release of superoxide anion was studied by using
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