Disruption of Leptin Receptor–STAT3 Signaling Enhances Leukotriene Production and Pulmonary Host Defense against Pneumococcal Pneumonia

Abstract

The adipocyte-derived hormone, leptin, regulates energy homeostasis and the innate immune response. We previously reported that leptin plays a protective role in bacterial pneumonia, but the mechanisms by which leptin regulates host defense remain poorly understood. Leptin binding to its receptor, LepRb, activates multiple intracellular signaling pathways, including ERK1/2, STAT5, and STAT3. In this report, we compared the responses of wild type (WT) and s/s mice, which possess a mutant LepRb that prevents leptin induced STAT3 activation, to determine the role of this signaling pathway in pneumococcal pneumonia. Compared with WT animals, s/s mice exhibited greater survival and enhanced pulmonary bacterial clearance following an intratracheal challenge with Streptococcus pneumoniae. We also observed enhanced phagocytosis and killing of S.pneumoniae in vitro in alveolar macrophages (AM) obtained from s/s mice. Interestingly, the improved host defense and AM antibacterial effector functions in s/s mice were associated with increased cysteinyl-leukotriene production in vivo and in AMs in vitro. Augmentation of phagocytosis in AMs from s/s mice could be blocked using a pharmacologic cysteinyl-LT receptor antagonist. Phosphorylation of ERK1/2 and cPLA2α, known to enhance the release of arachidonic acid for subsequent conversion to LTs, was also increased in AMs from s/s mice stimulated with S.pneumoniae in vitro. These data indicate that ablation of LepRb-mediated STAT3 signaling and the associated augmentation of ERK1/2, cPLA2α, and cysteinyl-LT synthesis confers resistance to s/s mice during pneumococcal pneumonia. These data provide novel insights into the intracellular signaling events by which leptin contributes to host defense against bacterial pneumonia.

Obesity: Changing Asthma in the 21st Century

“…In combination studies, in contrast, the magnitude of improvement with active drug on top of background therapy appears to be attenuated, and the placebo-treated subjects, who continue to receive background therapy, generally remain stable or even further improve slightly; since they are less likely to deteriorate during a short trial, the magnitude of placebo-corrected treatment effect is attenuated. This explains the consistent finding of an average treatment effect of 20-25 m in combination trials (7,12,13) as compared with values twice that in most de novo treatment trials. Furthermore, there may be a dissociation between harder outcomes such as mortality and the magnitude of improvement in 6MWD with combination therapy (13).…”

“…Mancuso and colleagues have shown that alveolar macrophage function is altered in leptin-deficient mice: macrophages from obese mice have impaired phagocytosis and abnormalities in leukotriene production (11,12). This has important implications for host defense.…”

Role of Leptin-Mediated Colonic Inflammation in Defense against Clostridium difficile Colitis

“…Binding of leptin to its receptor (LepRb) leads to activation of multiple signaling pathways via phosphorylation of different conserved tyrosine residues in the intracellular domain (50,51). In mouse models of Gram-negative bacterial pneumonia, leptin signaling via the STAT3 pathway (Y1138S-STAT3 mutant mice [S1138 mice]) was protective (32). Studies from our laboratory have also shown that S1138 mice had worse disease in a mouse model of amebic colitis (29).…”

“…Leptin was protective in the murine model via activation of STAT3/SOCS3 and SHP2/ mitogen-activated protein kinase (MAPK)-extracellular signalregulated kinase (ERK) signaling pathways downstream of the leptin receptor (29). Other investigators have shown an association of the Q223R mutation with the increased susceptibility of patients to bacterial peritonitis (42), and in murine models, leptin has been shown to protect from bacterial pneumonia (30,32).…”

“…It is now known that leptin is important in defense against infectious diseases (28)(29)(30). Humans with leptin deficiency have an increased incidence of infection (28), and mice with leptin deficiency (ob/ob) or leptin receptor deficiency (db/db) have increased susceptibility to pneumonia, listeriosis, and amebiasis (29,30,32,33). Leptin is also expressed in the colon of patients with Crohn's disease and ulcerative colitis (34,35).…”