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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

Correspondence to Dr. Luciano Ottonello, Dipartimento di Medicina Interna e Specialità Mediche, Viale Benedetto XV n. 6, I-16132 Genova, Italy. Phone: +39-010-3538686; Fax: +39-010-3538686; E-mail: otto{at}csita.unige.it

ABSTRACT. Leptin is a pleiotropic molecule involved in energy homeostasis, hematopoiesis, inflammation, and immunity. Hypoleptinemia characterizing starvation has been strictly related to increased susceptibility to infection secondary to malnutrition. Nevertheless, ESRD is characterized by high susceptibility to bacterial infection despite hyperleptinemia. Defects in neutrophils play a crucial role in the infectious morbidity, and several uremic toxins that are capable of depressing neutrophil functions have been identified. Only a few and contrasting reports about leptin and neutrophils are available. This study provides evidence that leptin inhibits neutrophil migration in response to classical chemoattractants. Moreover, serum from patients with ESRD inhibits migration of normal neutrophils in response to N-formyl-methionyl-leucyl-phenylalanine with a strict correlation between serum leptin levels and serum ability to suppress neutrophil locomotion. Finally, the serum inhibitory activity can be effectively prevented by immune depletion of leptin. The results also show, however, that leptin by itself is endowed with chemotactic activity toward neutrophils. The two activities—inhibition of the cell response to chemokines and stimulation of neutrophil migration—could be detected at similar concentrations. On the contrary, neutrophils exposed to leptin did not display detectable [Ca²⁺]_i mobilization, oxidant production, or ₂-integrin upregulation. The results demonstrate that leptin is a pure chemoattractant devoid of secretagogue properties that are capable of inhibiting neutrophil chemotaxis to classical neutrophilic chemoattractants. Taking into account the crucial role of neutrophils in host defense, the leptin-mediated ability of ERSD serum to inhibit neutrophil chemotaxis appears as a potential mechanism that contributes to the establishment of infections in ERSD.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673