Leptin Indirectly Activates Human Neutrophils via Induction of TNF-α

Abstract

Leptin, the satiety hormone, appears to act as a link between nutritional status and immune function. It has been shown to elicit a number of immunoregulatory effects, including the promotion of T cell proliferative responses, and the induction of proinflammatory cytokines. Leptin deficiency is associated with an increased susceptibility to infection. As polymorphonuclear neutrophils (PMN) play a major role in innate immunity and host defense against infection, this study evaluated the influence of leptin on PMN activation. The presence of leptin receptor in human PMN was determined both at mRNA and protein levels, and the effect of leptin on PMN activation, as assessed by CD11b expression, was evaluated using flow cytometry. In contrast to monocytes, which express both the short and long forms of the leptin receptor (Ob-Ra and Ob-Rb, respectively), PMN expressed only Ob-Ra. Leptin up-regulated the expression of CD11b, an early marker of PMN activation, on PMN in whole blood, yet it had no effect on purified PMN, even those treated by submaximal doses of TNF-α or PMA. The kinetics of leptin-induced activation in whole blood were consistent with an indirect effect mediated by monocytes, and 71% of the leptin-stimulatory effect on PMN was blocked by a TNF-α inhibitor. Leptin-mediated induction of CD11b expression was observed when purified PMN were coincubated with purified monocytes. In conclusion, although leptin activates PMN, it does so indirectly via TNF-α release from monocytes. These findings provide an additional link among the obesity-derived hormone leptin, innate immune function, and infectious disease.

Effects of Leptin and Tumor Necrosis Factor-.ALPHA. on Degranulation and Superoxide Production of Polymorphonuclear Neutrophils from Holstein Cows

“…The characteristics were consistent with the results reported by Zarkesh-Esfahani et al [23] showing that leptin has no direct effect on human PMN activation, and also those by Ottonello et al [17] demonstrating that leptin shows no secretagogue properties such as superoxide production in human PMN. However, these are rather conflicting with the reports by Caldefie-Chezet et al [4,5] who demonstrated that leptin is capable of inducing hydrogen peroxide and enhancing PMA-induced superoxide produc- Fig.…”

“…One noticeable difference between human and bovine PMN is that human PMN express only a short isoform of leptin receptor (Ob-Ra) lacking the large part of the intracellular domain [23], whereas bovine PMN expressed a long isoform of leptin receptor (Ob-Rb). We therefore speculate, although leptin had no effect on degranulation and superoxide production, it might influence bovine PMN functions, such as chemotaxis as observed in human PMN [17].…”

“…Partially contradictory to these reports, Ottonello et al [17] showed that leptin is a pure chemoattractant for human PMN, without having secretagogue properties such as superoxide production. However, Zarkesh-Esfahani et al [23] failed to observe any direct effect of leptin on human PMN activation, such that leptin does not induce the upregulation of CD11b expression, while tumor necrosis factor-α (TNF-α) up-regulates the expression of CD11b.…”

Leptin and mTOR: Partners in metabolism and inflammation

“…11 In macrophages, leptin acts as a potent chemoatractant and induces the production of inflammatory mediators including LTB 4 , TNFα and IL-6 among others. [12][13][14] Lymphocytes are also activated by leptin, which stimulates the proliferation of Th1 cells, leading to increased production of IL-1 and IFNγ. Such activation may play a role on the development of autoimmune diseases.…”

Airway inflammation is augmented by obesity and fatty acids in asthma

“…Leptin is secreted 2-3 times more highly from subcutaneous than from visceral adipose tissue and correlates more strongly with adiposity in females [12,17]. Leptin promotes T-helper type 1 cell differentiation and increases activation of neutrophils via tumour necrosis factor (TNF)-a [18]. Indeed, in a mouse pneumococcal pneumonia model, exogenous leptin stimulated the innate immune response leading to increased neutrophils and IL-6 in bronchoalveolar lavage fluid [19].…”