RGD Reference Report - Disruption of leptin receptor-STAT3 signaling enhances leukotriene production and pulmonary host defense against pneumococcal pneumonia. - Rat Genome Database

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Disruption of leptin receptor-STAT3 signaling enhances leukotriene production and pulmonary host defense against pneumococcal pneumonia.

Authors: Mancuso, P  Peters-Golden, M  Goel, D  Goldberg, J  Brock, TG  Greenwald-Yarnell, M  Myers MG, JR 
Citation: Mancuso P, etal., J Immunol. 2011 Jan 15;186(2):1081-90. Epub 2010 Dec 10.
RGD ID: 5128846
Pubmed: PMID:21148797   (View Abstract at PubMed)
PMCID: PMC3133444   (View Article at PubMed Central)
DOI: DOI:10.4049/jimmunol.1001470   (Journal Full-text)

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 study, we compared the responses of wild-type 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 wild-type animals, s/s mice exhibited greater survival and enhanced pulmonary bacterial clearance after an intratracheal challenge with Streptococcus pneumoniae. We also observed enhanced phagocytosis and killing of S. pneumoniae in vitro in alveolar macrophages (AMs) obtained from s/s mice. Notably, 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-leukotriene receptor antagonist. Phosphorylation of ERK1/2 and cytosolic phospholipase A(2) alpha, known to enhance the release of arachidonic acid for subsequent conversion to leukotrienes, 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, cytosolic phospholipase A(2) alpha, and cysteinyl-leukotriene 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Pneumococcal Pneumonia  ISOLepr (Mus musculus)5128846; 5128846 RGD 
Pneumococcal Pneumonia  IMP 5128846 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Lepr  (leptin receptor)

Genes (Mus musculus)
Lepr  (leptin receptor)

Genes (Homo sapiens)
LEPR  (leptin receptor)

Objects referenced in this article
Gene LEP leptin Homo sapiens
Gene Lep leptin Mus musculus
Gene Lep leptin Rattus norvegicus

Additional Information