Ottonello L, Gnerre P, Bertolotto M, et al: Leptin as a uremic toxin interferes with neutrophil chemotaxis

Dipartimento di Medicina Interna e specialità mediche (DIMI), Università degli Studi di Genova, Genova, Liguria, Italy
Journal of the American Society of Nephrology (Impact Factor: 9.47). 10/2004; 15(9):2366-72. DOI: 10.1097/01.ASN.0000139321.98029.40
Source: PubMed

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 [Ca(2+)](i) mobilization, oxidant production, or beta(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.

  • Source
    • "Moreover, leptin is secreted exclusively by adipocytes and is capable of linking metabolism and immune homeostasis (Matarese and La Cava, 2004). It has been reported to be also a chemoattractant for neutrophils (Ottonello et al., 2004) as well as for monocytes and macrophages (Gruen et al., 2007). In the present study, the larger adipocyte size of s.c. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The present study aimed to investigate whether phagocytic immune cells infiltrate into bovine adipose tissue (AT) and to study the effects of lactation and conjugated linoleic acid (CLA) supplementation on the invasion of phagocytic immune cells into different s.c. and visceral (v.c.) fat depots of primiparous dairy cows during the first 105 d in milk (DIM). German Holstein-Friesian cows (HF; n = 25) with a mean body condition score of 3.0 were divided into a control (CON) and a CLA group. From 1 DIM until sample collection, CLA cows were fed 100 g of CLA supplement/d (about 6% of c9,t11 and t10,c12 isomers each), whereas the CON cows received 100 g/d of a fatty acid mixture instead of CLA. The CON cows (n = 5 each) were slaughtered at 1, 42, and 105 DIM, and the CLA cows (n = 5 each) were slaughtered at 42 and 105 DIM. Adipose tissues (n = 150) from 3s.c. (tailhead, withers, and sternum) and 3 v.c. (omental, mesenteric, and retroperitoneal) depots were sampled. In addition, s.c. tailhead biopsies were collected by repeated surgical biopsies (3 samplings within 7 wk; n = 36) from 12 nonpregnant, nonlactating Simmental heifers (SM; mean body condition score = 5.0) fed diets of varying energy density to compare the changes in phagocytic immune cell infiltration with early lactating cows. Immunohistochemical analyses of different fat depots revealed a low incidence of phagocytic immune cell infiltration in early lactating cows. The portion of infiltrating macrophages (CD68+) in a few positive AT samples of HF cows was slightly lower in s.c. than v.c. fat and was positively correlated with both empty body weight and adipocyte size. However, no differences with regard to DIM and CLA supplementation were observed in HF cows. Increased accumulation of phagocytic immune cells, albeit at low cell numbers, in nonpregnant, over-conditioned SM heifers might be related to larger adipocytes secreting higher amounts of chemoattractant adipokines compared with the early lactating cows. In conclusion, the extent of fatness in HF cows may not be high enough to stimulate significant infiltration of phagocytic cells in AT and, therefore, these immune cells might have no major role in the immunologic and metabolic adaptations of AT during early lactation.
    Journal of Dairy Science 06/2012; 95(6):3032-44. DOI:10.3168/jds.2011-4856 · 2.55 Impact Factor
  • Source
    • "This group suggested that leptin could mediate the recruitment of macrophages in adipose tissue. Surmi and Hasty [5] proposed a probable mediation over leptin as well, since it has been reported to work as a chemoattractant for monocytes and macrophages [16], for neutrophils [17], and for cancer cells [18]. Leptin is known to correlate with the amount of adipose tissue [19] but morbid obesity in mice and human has been also reported in leptin deficiency [5]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Studies report on the association between obesity and oxidative stress, with and without additional diseases. Macrophages in adipocytes, and hypoxia in adipose tissue have been suggested to explain how obesity can relate to oxidative stress. The straight line hypothesis using the lactic acid trap construct has been put forward to explain how proton imbalance can relate to obesity. Proton imbalance has been also reported to associate with the production of reactive oxygen species by inhibition of mitochondrial energy production. This review brings together existing literature and concepts to explain how obesity can relate to oxidative stress via protons, uniquely for itself or, as often observed, in conglomeration of additional diseases.
    Medical Hypotheses 02/2010; 75(1):59-64. DOI:10.1016/j.mehy.2009.12.034 · 1.07 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Die Lebenserwartung urämischer Patienten ist deutlich reduziert, wobei kardiovaskuläre Erkrankungen und Ereignisse mehr als 50% der Todesfälle in dieser Patientenpopulation ausmachen. Das 5-Jahres-Überleben von Dialysepatienten ist mitunter schlechter als bei Patienten mit soliden Tumoren. In den letzten Jahren ist außerdem realisiert worden, dass bereits eine leichte Einschränkung der Nierenfunktion einem releventen und unabhängigen Mortalitätsrisikofaktor entspricht. Letztlich stellt eine akzeleriert ablaufende Athero- und Arteriosklerose das hauptsächliche morphologische Korrelat dieser insbesondere kardiovaskulären Übersterblichkeit in der Urämie dar, zusätzlich findet sich aber auch eine hohe Prävalenz von arterieller Hypertonie im Kontext mit Volumenüberladung und linksventrikulärer Hypertrophie. Für Shuntplanung und-chirurgie spielen insofern die häufig schwerwiegend vorgeschädigten Gefäße und die potenziell vorbestehende Herzinsuffizienz eine relevante Rolle.
Show more