Leptin improves pulmonary bacterial clearance and survival in ob/ob mice during pneumococcal pneumonia

Department of Environmental Health Sciences, Ann Arbor, MI, USA.
Clinical & Experimental Immunology (Impact Factor: 3.28). 12/2007; 150(2):332-9. DOI: 10.1111/j.1365-2249.2007.03491.x
Source: PubMed

ABSTRACT The 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 leptin-deficient 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)-alpha, macrophage inflammatory peptide (MIP)-2 [correction added after online publication 28 September 2007: definition of MIP corrected], prostaglandin E(2) (PGE(2)), 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 H(2)O(2) 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.

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Available from: Peter Mancuso, Aug 17, 2015
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    • "Furthermore, higher rates of respiratory, periodontal and skin infections occur in the obese population (Al Zahrani et al., 2003; Garcia, 2002; Sabato et al., 2006; Salerno et al., 2004; Thorsteinsdottir et al., 2005; Wood et al., 2003). An altered immune response to infection has also been observed in several genetic animal models of obesity, including ob/ob and db/db mice, and the Zucker fa/fa rat (Faggioni et al., 1997; Faggioni et al., 1999; Ivanov et al., 2001; Ivanov and Romanovsky, 2002; Lugarini et al., 2005; Mancuso et al., 2002; Rosenthal et al., 1996; Ordway et al., 2008; Hsu et al., 2007; Ikejima et al., 2005; Park et al., 2009; Wehrens et al., 2008; O'Connor et al., 2005; Plotkin et al., 1996). These animals are obese owing to either a deficiency in the adipokine leptin (ob/ob) or a defective leptin receptor (db/db and fa/fa). "
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    • "A considerable body of previously published observations suggest that leptin may regulate immune function (Lam and Lu, 2007) presumably via modulation of the autonomic nervous system. Mancuso and colleagues reported that leptin deficiency leads to weakened immune defense in mouse models of pneumonia and that leptin replacement provides benefits for the host defense in these models (Mancuso et al., 2002; Mancuso et al., 2006; Hsu et al., 2007). Other studies observed a weakened defense of leptin-deficient mice against mycobacterium tuberculosis and lipopolysaccharides (Faggioni et al., 1999; Wieland et al., 2005) as well as hepatic effects of listeria infection (Ikejima et al., 2005). "
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    ABSTRACT: Exposure to cigarette smoke (CS) is associated with increased risk of many infectious diseases including those caused by Streptococcus pneumoniae. Such pneumococcal infections are the leading cause of community-acquired pneumonia and deaths from invasive bacterial infections. Since CS exposure also impairs the function of the alveolar macrophage (AM), a cell central to innate host defense in the lung, we used in vivo and in vitro approaches to determine the effects of CS exposure in a murine model of pneumococcal pneumonia, and to elucidate how CS-mediated impairment of AM function might contribute to this relationship. Mice exposed to CS over 5 weeks developed more serious infections, with 4-fold and 35-fold higher pulmonary bacterial burdens at 24 hr and 48 hr post-infection, respectively. In separate experiments, we compared the effects of low-tar versus regular cigarettes on cellular recruitment and AM function, finding no evidence to support the perception that low-tar cigarettes might be less harmful. In vitro, AMs from CS-exposed animals displayed impaired cytokine production following pneumococcal challenge and reduced phagocytosis of bacteria but not IgG-opsonized microspheres, indicating intact FcR-mediated phagocytosis. To remove possible effects from other cells, naive AMs were treated in vitro with cigarette smoke conditioned media (CSCM), yielding similar impairments in phagocytosis that were specific to complement-opsonized pneumococcus, but no impairment in FcR-mediated microsphere phagocytosis. However in another experiment, CSCM-pretreated rat AMs did display impaired phagocytosis of IgG-opsonized E.coli, suggesting CS may interfere with TLR-mediated bacterial recognition. CSCM pretreatment impaired cytokine synthesis and reactive oxygen intermediate generation following challenge with LTA, a bacterial ligand for TLR2. However no differences were seen in TLR2 transcription suggesting that CSCM may impair TLR-mediated AM activation through disruption of downstream reactive oxygen intermediate-mediated signal transduction. Such a mechanism would indicate common themes underlying some of the diverse effects of CS exposure on immune function. Overall, the novel finding of impaired pulmonary innate host defense following CS exposure, and observation of AM bacterial recognition and phagocytosis impairments, may suggest new directions for understanding the effects of CS exposure on human health. Ph.D. Toxicology University of Michigan, Horace H. Rackham School of Graduate Studies
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