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Children's Hospital of Pittsburgh, Laboratory of Lung Immunology and Host Defense, Pittsburgh, Pennsylvania
Animal species have evolved elaborate repertoires of innate immunity, a subject that has received intense focus by the scientific community. The innate and adaptive immune systems in higher order eukaryotic organisms, such as mammals, are of critical importance in maintaining a balance between bacterial colonization at mucosal surfaces and host defense. This vital role has been elegantly shown to be operative in humans by studies that demonstrated increased susceptibility to disseminated mycobacterial infections in patients with mutations abrogating normal interferon receptor signaling (1, 2) or to Salmonella spp. in patients with interleukin (IL)-12/23R1 mutations (2, 3). In addition to innate immune sentinels such as the Toll-like receptor (TLR) family of proteins (4), organisms also require mechanisms to adjust to environmental stressors such as famine or starvation that have long been recognized as harbingers of illness (5). This fact was eloquently proven by Moret and Schmid-Hempel who found shortened survival of bumblebees in a state of starvation compared with health after exposure to lipopolysaccharide (6). Starvation continues to be a global health concern, and despite advances in health care delivery and critical care medicine, acute starvation is a common occurrence in hospitals.
Nature has its own mechanism of dealing with acute starvation. Important insights into this phenomenon have been recently provided by discovery of the hormone leptin. Leptin is secreted by adipose tissue and consists of a highly conserved 167-amino-acid sequence (7, 8). It is a product of the Ob gene, which was initially discovered in relation to appetite control at the arcuate nucleus in the hypothalamus. The Ob gene was linked to the weight gain and obesity that is the phenotype of the Ob/Ob mouse, which has a mutation in leptin (7). In the setting of acute starvation, leptin levels fall significantly. Leptin therefore appears to be a critical regulator of body weight by inhibiting food intake and stimulating energy expenditure (7).
Although leptin was initially described in the context of nutrition, Lord and coworkers, in 1998, showed that leptin also regulates adaptive T-cell responses. Leptin increases proliferative responses of both naive and memory T cells, enhances Th1 responses, and suppresses Th2 cytokine production (9). In addition to activity on T cells, leptin also can participate in the regulation of the proinflammatory cytokines tumor necrosis factor (TNF-) and IL-6 by monocytes (10). Consistent with these data, leptin receptors (OB-R) are expressed on subpopulations of monocytes, infiltrating tissue neutrophils and, to a lesser extent, lymphocytes (10). OB-R is a transmembrane protein with five different isoforms resulting from alternative splicing (11). The long form of leptin receptor (OBRl) consists of 304 cytoplasmic residues, and is presumed to possess the signaling capacity. Fong and colleagues localized the leptin binding site on leptin receptor to residues 323–640 (12). Leptin is member of the four- helix bundle of cytokines similar to IL-6 and IL-12 (11). Ligand binding of leptin to OBRl can activate Janus kinase 2 and STAT3 signaling pathways (12).
Leptin's role in the pulmonary immune system has only recently been studied in any detail. The study published in this issue of the Journal (pp. 212–218) by Mancuso and colleagues (13) highlights the intricate and important role leptin might play in lung host defense, particularly in the setting of acute starvation. This group had previously shown that the leptin-deficient ob/ob mice have increased mortality and defective host resistance to pulmonary Klebsiella pneumoniae infection (14). In particular, leptin-deficient mice displayed impaired TNF- and IL-12 responses as well as decreased phagocytic capacity of alveolar macrophages (14). In the current study, Mancuso and colleagues show that serum leptin levels are reduced in acutely fasted mice, but these mice still maintained serum glucose concentrations at the expense of only mildly elevated corticosterone levels. There was reduced clearance of Streptococcus pneumoniae in fasted mice, which was associated with reduced recruitment of neutrophils into the lungs, as well as diminished expression of IL-6, TNF-, and leukotriene B4 (LTB4). Importantly, administering exogenous leptin to target serum prefasting levels, the authors demonstrated that leptin could restore bacterial clearance in the setting of acute starvation. Leptin also reduced systemic corticosterone levels and augmented pulmonary neutrophil recruitment in response to S. pneumoniae challenge as well as alveolar macrophage production of LTB4.
The information provided by Mancuso and colleagues regarding the role of leptin in pulmonary host defense and cytokine/chemokine regulation suggests new therapeutic approaches for the critically ill. But will leptin emerge as immunotherapy for patients with malnutrition How safe and helpful will it be in malnourished patients in the intensive care unit with organ dysfunction Further studies in experimental models of sepsis, such as cecal ligation and puncture, may shed light on these issues. There are a number of additional future questions that need exploration before leptin becomes a therapeutic option. It is important to obtain more direct evidence of this hormone's involvement in pulmonary tissue by delineating the expression and distribution of its receptor isoforms in the lung. What would happen if the lungs were exposed to supranormal serum concentrations of this hormone Would elevated levels of this peptide result in exaggerated inflammatory responses Despite these concerns, the data obtained to date clearly set the stage for further investigation of leptin immunotherapy in high-risk patient populations.
FOOTNOTES
Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
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