Ablation of Leptin Receptor-Mediated ERK Activation Impairs Host Defense against Gram-Negative Pneumonia

Abstract

The adipocyte-derived hormone, leptin, plays an important role in regulating 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 antibacterial functions in vitro. l/l mice exhibited increased mortality and impaired pulmonary bacterial clearance following intratracheal challenge with Klebsiella pneumoniae. The synthesis of cysteinyl-LTs was reduced and that of PGE2 enhanced in alveolar macrophages in vitro and the lungs of l/l mice following 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 PGE2 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.

TREM‐2 Promotes Macrophage‐Mediated Eradication of Pseudomonas aeruginosa via a PI3K/Akt Pathway

“…While in dendritic cells, TREM-2/DAP12 stimulation is through activation of ERK, but independent of NF-jB and P38 stress-activated protein kinase [52]. Studies have demonstrated that Akt is required in the killing of Neisseria gonorrhoeae [29] and Erk is involved in host defence against Klebsiella pneumoniae [54], whereas JNK is reported to inhibit macrophage killing of Staphylococcus aureus [55] and p38 is shown to attenuate macrophage antibacterial activities against Streptococcus pneumoniae [56]. Our data showed that silencing of TREM-2 inhibited Akt phosphorylation, but had no effect on activation of ERK, P38 and JNK.…”

Ablation of the leptin receptor in myeloid cells impairs pulmonary clearance ofStreptococcus pneumoniaeand alveolar macrophage bactericidal function

“…We have previously used leptin receptor mutant mice (s/s and l/l) to identify which LepRb-mediated intracellular signaling events contribute to the host response to bacterial pneumo-nia (35,36). Using the s/s mouse, which cannot signal through the LepRb¡-STAT3 pathway and is obese, we observed that leptin-mediated ERK activation enhances AM leukotriene (LT) synthesis, AM phagocytosis, and bacterial killing, resulting in protection against pneumococcal pneumonia in vivo (36).…”

Proteins in Preservation Fluid as Predictors of Delayed Graft Function in Kidneys from Donors after Circulatory Death

“…A synergetic role for GM-CSF and osteopontin in the recruitment of macrophages and monocytes to the implanted kidney, which promotes remodeling and better engraftment, is conceivable. A possible mechanism skewing infiltrated monocytes to M2 (regenerative) macrophages to promote IF is supported by the lower leptin levels in this group, as, besides an "energy indicator," leptin has been reported to promote a proinflammatory environment and skew macrophages toward the inflammatory M1 phenotype, either directly or through mast cells (40)(41)(42)(43).…”