Leptin is an eosinophil survival factor
Leptin regulates food intake, as well as metabolic, endocrine, and immune functions. It exerts proliferative and antiapoptotic activities in a variety of cell types, including T cells. Leptin also stimulates macrophages and neutrophils, and its production is increased during inflammation.
We sought to examine the expression of leptin receptors on eosinophils and the effect of recombinant leptin on proapoptotic pathways in these cells.
The presence of leptin receptor was examined by means of RT-PCR and immunofluorescence analysis in freshly isolated blood eosinophils and tissue eosinophils. The effect of recombinant leptin on apoptotic pathways in eosinophils was studied by using flow cytometric, immunoblotting, and immunofluorescence techniques.
Human eosinophils express leptin surface receptors under in vitro and in vivo conditions, and leptin delays apoptosis of mature eosinophils in vitro. The antiapoptotic effects of leptin were concentration dependent and blocked by an anti-leptin receptor mAb. The efficacy of leptin to block eosinophil apoptosis was similar to that of GM-CSF. Leptin delayed the cleavage of Bax, as well as the mitochondrial release of cytochrome c and second mitochondria-derived activator of caspase, suggesting that it blocks proapoptotic pathways proximal to mitochondria in eosinophils. Using pharmacological inhibitors, we obtained evidence that leptin initiates a signaling cascade involving phosphatidylinositol-3-OH kinase and mitogen-activated protein kinase-dependent pathways in eosinophils.
Leptin is a survival cytokine for human eosinophils, a finding with potential pathologic relevance in allergic and parasitic diseases.
Available from: Sang-Ha Kim
- "In light of the purported association between obesity and asthma, several recent studies suggested that adipokines can affect the survival and function of eosinophils, focusing on chemotactic responses and adhesion activities in the pathogenesis of asthma. Leptin directly activates eosinophils and delays spontaneous apoptosis of mature eosinophils using surface receptors expressed on human eosinophils.38 Leptin thus may serve as an important eosinophil survival factor through anti-apoptotic activity. "
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ABSTRACT: Increasing epidemiological data identify a link between obesity and asthma incidence and severity. Based on experimental data, it is possible that shared inflammatory mechanisms play a role in determining this linkage. Although controversial, the role of adipokines may be central to this association and the maintenance of the asthma phenotype. While leptin and adiponectin have a causal link to experimental asthma in mice, data in humans are less conclusive. Recent studies demonstrate that adipokines can regulate the survival and function of eosinophils and that these factors can affect eosinophil trafficking from the bone marrow to the airways. In addition, efferocytosis, the clearance of dead cells, by airway macrophages or blood monocytes appears impaired in obese asthmatics and is inversely correlated with glucocorticoid responsiveness. This review examines the potential mechanisms linking obesity to asthma.
Allergy, asthma & immunology research 05/2014; 6(3):189-195. DOI:10.4168/aair.2014.6.3.189 · 2.43 Impact Factor
Available from: Vanessa Pinho
- "For instance some members of the Bcl-2 family are involved in eosinophil survival. Specifically , increased expression of Bcl-X L (Dibbert et al., 1998), maintained Bid cleavage (Segal et al., 2007), inhibition of Bax translocation to the mitochondria (Dewson et al., 2001), and delayed Bax cleavage (Conus et al., 2005) result in maintained mitochondrial integrity and inhibition of caspase activation (Dewson et al., 2001; Conus et al., 2005). Likewise, neutrophils express anti-apoptotic members (Bcl-X L , Bcl2A1 and Mcl-1) as well as pro-apoptotic proteins (Bax, Bak, Bid, Bim and Puma) and those proteins regulate constitutive as well as inducible apoptosis/survival pathways (Weinmann et al., 1999; Moulding et al., 2001; Guo et al., 2006; Cowburn et al., 2011). "
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ABSTRACT: Inflammation is a beneficial host reaction to tissue damage and has the essential primary purpose of restoring tissue homeostasis. Inflammation plays a major role in containing and resolving infection and may also occur under sterile conditions. The cardinal signs of inflammation dolor, calor, tumor and rubor are intrinsically associated with events including vasodilatation, edema and leukocyte trafficking into the site of inflammation. If uncontrolled or unresolved, inflammation itself can lead to further tissue damage and give rise to chronic inflammatory diseases and autoimmunity with eventual loss of organ function. It is now evident that the resolution of inflammation is an active continuous process that occurs during an acute inflammatory episode. Successful resolution requires activation of endogenous programs with switch from production of pro-inflammatory towards pro-resolving molecules, such as specific lipid mediators and annexin A1, and the non-phlogistic elimination of granulocytes by apoptosis with subsequent removal by surrounding macrophages. These processes ensure rapid restoration of tissue homeostasis. Here, we review recent advances in the understanding of resolution of inflammation, highlighting the pharmacological strategies that may interfere with the molecular pathways which control leukocyte survival and clearance. Such strategies have proved beneficial in several pre-clinical models of inflammatory diseases, suggesting that pharmacological modulation of the resolution process may be useful for the treatment of chronic inflammatory diseases in humans.
Pharmacology [?] Therapeutics 04/2013; 139(13). DOI:10.1016/j.pharmthera.2013.04.006 · 9.72 Impact Factor
Available from: Stephane Dragon
- "Leptin has been shown to augment bacterial phagocytosis, intracellular hydrogen peroxide production and chemotactic migration of neutrophils , . Interestingly, leptin was also shown to enhance the cytokine release, migration, and survival of eosinophils, collectively suggesting a role in allergic inflammation , . To date, however, the expression and function of leptin on neutrophils purified from children in context of allergic airway disease has not been studied. "
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ABSTRACT: Previous studies have shown that delayed neutrophil apoptosis is associated with chronic airway diseases. Leptin is an adipocyte-derived hormone that acts as a regulator of energy homeostasis and food intake. Emerging evidence suggests that leptin can regulate immune responses including the release of proinflammatory cytokines and protection of inflammatory cells from apoptosis. Serum leptin is increased during allergic reactions in the airways. However, the expression and function of leptin receptor in neutrophils isolated from children is not known.
Flow cytometry was used to detect leptin receptor expression in neutrophils isolated from allergic asthmatic (n = 14), allergic non asthmatic (n = 21), non allergic asthmatic (n = 7) and healthy children (n = 23); confocal laser scanning microscopy combined with immunofluorescence was performed to detect intracellular pool of leptin receptor; Annexin-V/PI staining and caspase 3 activity was used to determine neutrophil survival. Pharmacological inhibitors were utilized to understand the role of MAPK and NF-κB pathway in leptin-induced neutrophil survival.
A heterogeneous leptin receptor expression was observed on neutrophils isolated from children. Neutrophils isolated from healthy children expressed more leptin receptor than those from allergic asthmatic (P<0.05) but not allergic non-asthmatic (P>0.05) or non-allergic asthmatic children (n = 7, P>0.05). Neutrophils isolated from children express an intracellular pool of leptin receptor that was mobilized to the cell surface upon GM-CSF stimulation. Finally, leptin exhibited anti-apoptotic properties on neutrophils via NF-κB and MEK1/2 MAPK pathway. Collectively, our data suggest that leptin may enhance airway inflammation by promoting neutrophil survival.
PLoS ONE 01/2013; 8(1):e55249. DOI:10.1371/journal.pone.0055249 · 3.23 Impact Factor
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