Leptin is an adipocyte-derived hormone that is secreted in correlation with total body lipid stores. Serum leptin levels are lowered by the loss of body fat mass that would accompany starvation and malnutrition. Recently, leptin has been shown to modulate innate immune responses such as macrophage phagocytosis and cytokine synthesis in vitro. To determine whether leptin plays a role in the innate host response against Gram-negative pneumonia in vivo, we compared the responses of leptin-deficient and wild-type mice following an intratracheal challenge of Klebsiella pneumoniae. Following K. pneumoniae administration, we observed increased leptin levels in serum, bronchoalveolar lavage fluid, and whole lung homogenates. In a survival study, leptin-deficient mice, as compared with wild-type mice, exhibited increased mortality following K. pneumoniae administration. The increased susceptibility to K. pneumoniae in the leptin-deficient mice was associated with reduced bacterial clearance and defective alveolar macrophage phagocytosis in vitro. The exogenous addition of very high levels of leptin (500 ng/ml) restored the defect in alveolar macrophage phagocytosis of K. pneumoniae in vitro. While there were no differences between wild-type and leptin-deficient mice in lung homogenate cytokines TNF-α, IL-12, or macrophage-inflammatory protein-2 after K. pneumoniae administration, leukotriene synthesis in lung macrophages from leptin-deficient mice was reduced. Leukotriene production was restored by the addition of exogenous leptin (500 ng/ml) to macrophages in vitro. This study demonstrates for the first time that leptin-deficient mice display impaired host defense in bacterial pneumonia that may be due to a defect in alveolar macrophage phagocytosis and leukotriene synthesis.

Adipose tissue has traditionally been defined as connective tissue that stores excess calories in the form of triacylglycerol. However, the physiologic functions attributed to adipose tissue are expanding, and it is now well established that adipose tissue is an endocrine gland. Among the endocrine factors elaborated by adipose tissue are the adipokines; hormones, similar in structure to cytokines, produced by adipose tissue in response to changes in adipocyte triacylglycerol storage and local and systemic inflammation. They inform the host regarding long-term energy storage and have a profound influence on reproductive function, blood pressure regulation, energy homeostasis, the immune response, and many other physiologic processes. The adipokines possess pro- and anti-inflammatory properties and play a critical role in integrating systemic metabolism with immune function. In calorie restriction and starvation, proinflammatory adipokines decline and anti-inflammatory adipokines increase, which informs the host of energy deficits and contributes to the suppression of immune function. In individuals with normal metabolic status, there is a balance of pro- and anti-inflammatory adipokines. This balance shifts to favor proinflammatory mediators as adipose tissue expands during the development of obesity. As a consequence, the proinflammatory status of adipose tissue contributes to a chronic low-grade state of inflammation and metabolic disorders associated with obesity. These disturbances are associated with an increased risk of metabolic disease, type 2 diabetes, cardiovascular disease, and many other pathological conditions. This review focuses on the impact of energy homeostasis on the adipokines in immune function.

Leukotrienes are bronchoconstrictor and vasoactive lipid mediators that are targets in the treatment of asthma. Although they are increasingly recognized to exert broad proinflammatory effects, their role in innate immune responses is less well appreciated. These molecules are indeed synthesized by resident and recruited leukocytes during infection. Acting via cell surface G protein-coupled receptors and subsequent intracellular signaling events, they enhance leukocyte accumulation, phagocyte capacity for microbial ingestion and killing, and generation of other proinflammatory mediators. Interestingly, a variety of acquired states of immunodeficiency, such as HIV infection and malnutrition, are characterized by a relative deficiency of leukotriene synthesis. The data reviewed herein point to leukotrienes as underappreciated yet highly relevant mediators of innate immunity.

Leukotrienes (LTs) are lipid mediators that participate in inflammatory diseases and innate immune function. We sought to investigate the importance of LTs in regulating the microbicidal activity of alveolar macrophages (AMs) and the molecular mechanisms by which this occurs. The role of LTs in enhancing AM microbicidal activity was evaluated pharmacologically and genetically using in vitro challenge with Klebsiella pneumoniae. Exogenous LTs increased AM microbicidal activity in a dose-and receptor-dependent manner, and endogenous production of LTs was necessary for optimal killing. Leukotriene B 4 (LTB 4 ) was more potent than cysteinyl LTs. An important role for nicotinamide adenine dinucleotide (NADPH) oxidase in LT-induced microbicidal activity was indicated by the fact that bacterial killing was abrogated by the NADPH oxidase inhibitor diphenyleneiodonium (DPI; 10 M) and in AMs derived from gp91phox-deficient mice. By contrast, LT-induced microbicidal activity was independent of the generation of nitric oxide. LTs increased H 2 O 2 production, and LTB 4 was again the more potent agonist. Both classes of LTs elicited translocation of p47phox to the cell membrane, and LTB 4 induced phosphorylation of p47phox in a manner dependent on protein kinase C-␦ (PKC-␦) activity. In addition, the enhancement of microbicidal activity by LTs was also dependent on PKC-␦ activity. Our results demonstrate that LTs, especially LTB 4 , enhance AM microbicidal activity through the PKC-␦-dependent activation of NADPH oxidase. IntroductionPneumonia is the leading cause of death from infection in the United States, 1 and its global mortality is 4.3 million people per year. 2 This problem is compounded by growing numbers of immunosuppressed patients and multidrug-resistant microorganisms. Developing more effective agents for the prevention and treatment of pneumonia requires a better understanding of how innate pulmonary defense mechanisms are regulated.The alveolar macrophage (AM) patrols the epithelial surface of the distal lung and maintains sterility by phagocytosing and killing microorganisms. 3,4 AMs are the first line of defense against invading microorganisms and, as such, are capable of secreting cytokines, lipid mediators, and microbicidal molecules. Among the lipid mediators generated by AMs, the leukotrienes (LTs) play an important role in lung innate immunity, inducing neutrophil recruitment and enhancing macrophage antimicrobial functions. 5 LTs are derived from the metabolism of the cell-membrane fatty acid arachidonic acid (AA) through the enzyme 5-lipoxygenase (5-LO), in concert with its helper protein, 5-LO-activating protein (FLAP). 6 5-LO oxygenates AA to the intermediate 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which is either enzymatically reduced by 5-LO to the unstable epoxide leukotriene A 4 (LTA 4 ) or alternatively is reduced to 5-hydroxyeicosatetraenoic acid (5-HETE). LTA 4 can be hydrolyzed to form LTB 4 or can be conjugated with glutathione to form the cysteinyl LTs (cysLTs), LTC 4 , LTD 4 , and ...

SOCS1 and -3 proteins are released by alveolar macrophages into exosomes and microparticles, respectively, which are then taken up by alveolar epithelial cells, resulting in inhibition of STAT signaling. This process was dampened by exposure to cigarette smoke and may thus be important in suppressing airway inflammation.

During the last 40 years, there has been a world-wide increase in both the prevalence of obesity and an increase in the number of persons over the age of 60 due to a decline in deaths from infectious disease and the nutrition transition in low and middle income nations. While the increase in the elderly population indicates improvements in global public health, this population may experience a diminished quality of life due to the negative impacts of obesity on age-associated inflammation. Aging alters adipose tissue composition and function resulting in insulin resistance and ectopic lipid storage. A reduction in brown adipose tissue activity, declining sex hormones levels, and abdominal adipose tissue expansion occur with advancing years through the redistribution of lipids from the subcutaneous to the visceral fat compartment. These changes in adipose tissue function and distribution influence the secretion of adipose tissue derived hormones, or adipokines, that promote a chronic state of low-grade systemic inflammation. Ultimately, obesity accelerates aging by enhancing inflammation and increasing the risk of age-associated diseases. The focus of this review is the impact of aging on adipose tissue distribution and function and how these effects influence the elaboration of pro and anti-inflammatory adipokines.

The prevalence of obesity has increased dramatically worldwide, predisposing individuals to an increased risk of morbidity and mortality due to cardiovascular disease and type 2 diabetes. Less recognized is the fact that obesity may play a significant role in the pathogenesis of pulmonary diseases through mechanisms that may involve proinflammatory mediators produced in adipose tissue that contribute to a low-grade state of systemic inflammation. In animal models, inflammatory responses in the lung have been shown to influence the production of the adipocytokines, leptin and adiponectin, cytokines, acute phase proteins, and other mediators produced by adipose tissue that may participate in immune responses of the lung. An increased adipose tissue mass may also influence susceptibility to pulmonary infections, enhance pulmonary inflammation associated with environmental exposures, and exacerbate airway obstruction in preexisting lung disease. An increased understanding of the mechanisms by which obesity influences pulmonary inflammation may facilitate the development of novel therapeutic interventions for the treatment of lung disease.

SummaryThe adipocyte-derived hormone leptin is an important regulator of appetite and energy expenditure and is now appreciated for its ability to control innate and adaptive immune responses. We have reported previously that the leptindeficient ob/ob mouse exhibited increased susceptibility to the Gram-negative bacterium Klebsiella pneumoniae. In this report we assessed the impact of chronic leptin deficiency, using ob/ob mice, on pneumococcal pneumonia and examined whether restoring circulating leptin to physiological levels in vivo could improve host defences against this pathogen. We observed that ob/ob mice, compared with wild-type (WT) animals, exhibited enhanced lethality and reduced pulmonary bacterial clearance following Streptococcus pneumoniae challenge. These impairments in host defence in ob/ob mice were associated with elevated levels of lung tumour necrosis factor (TNF)-a, macrophage inflammatory peptide (MIP)-2 [correction added after online publication 28 September 2007: definition of MIP corrected], prostaglandin E2 (PGE2), lung neutrophil polymorphonuclear leukocyte (PMN) counts, defective alveolar macrophage (AM) phagocytosis and PMN killing of S. pneumoniae in vitro.Exogenous leptin administration to ob/ob mice in vivo improved survival and greatly improved pulmonary bacterial clearance, reduced bacteraemia, reconstituted AM phagocytosis and PMN H2O2 production and killing of S. pneumoniae in vitro. Our results demonstrate, for the first time, that leptin improves pulmonary bacterial clearance and survival in ob/ob mice during pneumococcal pneumonia. Further investigations are warranted to determine whether there is a potential therapeutic role for this adipokine in immunocompromised patients.