Leptin as regulator of pulmonary immune responses: Involvement in respiratory diseases

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Abstract

Leptin is an adipocyte-derived hormone, recognized as a critical mediator of the balance between food intake and energy expenditure by signalling through its functional receptor (Ob-Rb) in the hypothalamus. Structurally, leptin belongs to the long-chain helical cytokine family, and is now known to have pleiotropic functions in both innate and adaptive immunity. The presence of the functional leptin receptor in the lung together with evidence of increased airspace leptin levels arising during pulmonary inflammation, suggests an important role for leptin in lung development, respiratory immune responses and eventually pathogenesis of inflammatory respiratory diseases. The purpose of this article is to review our current understanding of leptin and its functional role on the different resident cell types of the lung in health as well as in the context of three major respiratory conditions being chronic obstructive pulmonary disease (COPD), asthma, and pneumonia.

Introduction

Leptin is a 16 kDa non-glycosylated polypeptide encoded by the ‘obese’ (ob) gene [1]. Originally described as a hormone secreted by adipocytes in proportion to total fat mass, leptin was implicated in early studies as a critical mediator of the balance between food intake and energy expenditure by signalling through its functional receptor (Ob-Rb) in the hypothalamus [2], [3]. However, leptin belongs structurally to the long-chain helical cytokine family, which includes interleukin-6 (IL-6), G-CSF, and oncostatin M amongst others, and shares an extreme functional pleiotropy with many other members of this family. The near universal distribution of leptin receptors, including in the respiratory system, reflects a multiplicity of biological effects. Leptin has been reported to participate in diverse physiological functions in both the central nervous system and the periphery, including appetite and body mass control, metabolism, endocrine function, immune response, wound healing, reproduction, cardiovascular pathophysiology, and respiratory tissue development, remodelling, and function.

Adipocytes located in various fat depots are a major, but not sole source of leptin. Cells of the placenta [4], gastric mucosa [5], colon [6], mammary epithelium [7], pituitary, hypothalamus [8], skeletal muscle [9], [10], bone [11] and bone marrow [12] have also been shown to produce leptin in certain circumstances [2]. Leptin expression has also been described in the lung tissues of humans [13], baboons [14], mice [15], seals [16], and even Xenopus [17]. Recent studies have shown leptin secretion by human lung epithelial cell types, including bronchial epithelial cells (BEC) [13], [18], type II pneumocytes [13], and lipofibroblasts [19].

Leptin expression in adipocytes is regulated by food intake and circulating leptin levels have been shown to positively correlate with insulin levels. In addition, glucocorticoids appear to be potent regulators of leptin expression based on in vitro studies of isolated adipocytes [20], while a gender-related leptin regulation is suggested by the findings that leptin expression is increased by ovarian sex steroids and inhibited by testosterone [21], [22], [23]. Other modulators of leptin expression include a wide range of pro-inflammatory cytokines – including TNFα – which are known to acutely increase leptin synthesis in adipocytes [24], [25], whereas chronic stimulation with such cytokines appears to lead to a suppression of leptin synthesis [26], [27]. In the normal lung, numerous cell types display high levels of Ob-Rb [28], [29], and specific leptin-binding sites have been identified in both bronchial and alveolar epithelial cells [30], [31], [32], airway smooth muscle cells, and (infiltrating) inflammatory cells. Multiple observations that leptin is actually present in induced sputum [33], [34], [35], proximal airway biopsies [18], bronchoalveolar lavage (BAL) fluid [36], [37], and peripheral lung tissue [13] of patients with lung disease, strongly suggest the lung as a peripheral site of action for leptin. The present review aims to summarize our current understanding on leptin and its functional role in the respiratory system in homeostasis and inflammatory lung diseases.

Section snippets

Leptin signal transduction

Leptin acts via the Ob-R transmembrane receptor, which shares structural similarities with the class I cytokine receptor superfamily [38], [39]. Members of this family have signature extracellular domains (so-called cytokine receptor homology or CRH domains) characterised by a set of four cysteine residues and the highly conserved Trp-Ser-Xaa-Trp-Ser motif. Several alternative splice isoforms of Ob-R exist in humans and rodents, designated Ob-Ra, Ob-Rb, Ob-Rc, Ob-Rd, Ob-Re (only in rats and

Role of leptin in respiration and lung development

Multiple studies have shown that leptin participates in the regulation of pulmonary development and remodelling. Huang et al. characterized the effect of leptin deficiency on postnatal lung development in leptin-deficient (ob/ob) mice [47] and showed that the lung volume and alveolar surface area were lower in obese mice compared with wild-type and heterozygote (ob/+) mice, and that the alveolar size did not increase with age. Leptin replacement in ob/ob mice resulted in increased lung volume,

Role of leptin in inflammatory lung diseases

Numerous studies demonstrate that leptin has a potentiating role in the function of both innate and adaptive immunity [55], making it an ideal candidate for a central role in inflammatory respiratory diseases such as COPD, asthma, and pneumonia. Leptin is known to stimulate neutrophil and macrophage chemotaxis and enhance functional responses such as oxidative burst [56], phagocytosis [57] and cytokine secretion [58], [59]. Neutrophil chemotaxis response was shown to be blunted in

Conclusions

The pleiotropic functions of leptin are of growing interest, and significant progress has been made in understanding leptin's role in inflammatory respiratory diseases and the underlying immune response. As a type-I cytokine, leptin appears to serve as far more than a satiety hormone for the regulation of food intake and energy expenditure. The presence of the functional leptin receptor in the lung on both leukocytes and lung epithelial cells together with evidence of local leptin production in

Acknowledgements

This study was supported by an unrestricted grant from De Weijerhorst Foundation, Maastricht, The Netherlands and a Concerted Research Action of the University of Ghent (BOF/GOA 01251504 and 01G01009), Ghent, Belgium. K.R. Bracke is a post-doctoral researcher of the Fund for Scientific Research in Flanders (FWO Vlaanderen).

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