The adipocyte-derived
hormone leptin plays an important role in regulation of energy homeostasis and the innate immune response against
bacterial infections.
Leptin's actions are mediated by signaling events initiated by phosphorylation of
tyrosine residues on the long form of the
leptin receptor. We recently reported that disruption of
leptin receptor-mediated STAT3 activation augmented host defense against
pneumococcal pneumonia. In this report, we assessed
leptin receptor-mediated ERK activation, a pathway that was ablated in the l/l mouse through a mutation of the
tyrosine 985 residue in the
leptin receptor, to determine its role in host defense against
bacterial pneumonia in vivo and in alveolar macrophage (AM) antibacterial functions in vitro. l/l mice exhibited increased mortality and impaired pulmonary bacterial clearance after intratracheal challenge with Klebsiella pneumoniae. The synthesis of cysteinyl-
leukotrienes was reduced and that of
PGE(2) enhanced in AMs in vitro and the lungs of l/l mice after
infection with K. pneumoniae in vivo. We also observed reduced phagocytosis and killing of K. pneumoniae in AMs from l/l mice that was associated with reduced reactive
oxygen intermediate production in vitro. cAMP, known to suppress phagocytosis, bactericidal capacity, and reactive
oxygen intermediate production, was also increased 2-fold in AMs from l/l mice. Pharmacologic blockade of
PGE(2) synthesis reduced cAMP levels and overcame the defective phagocytosis and killing of bacteria in AMs from l/l mice in vitro. These results demonstrate that
leptin receptor-mediated ERK activation plays an essential role in host defense against
bacterial pneumonia and in leukocyte antibacterial effector functions.