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

Abstract

Leptin is a pleiotropic hormone produced by white adipose tissue that regulates appetite and many physiological functions, including the immune response to infection. Genetic leptin deficiency in humans and mice impairs host defenses against respiratory tract infections. Since leptin deficiency is associated with obesity and other metabolic abnormalities, we generated mice that lack the leptin receptor (LepRb) in cells of the myeloid linage (LysM-LepRb-KO) to evaluate its impact in lean metabolically normal mice in a murine model of pneumococcal pneumonia. We observed higher lung and spleen bacterial burdens in LysM-LepRb-KO mice following an intratracheal challenge with Streptococcus pneumoniae. Although numbers of leukocytes recovered from bronchoalveolar lavage fluid did not differ between groups, we did observe higher levels of pulmonary IL-13 and TNFα in LysM-LepRb-KO mice 48 h post infection. Phagocytosis and killing of ingested S. pneumoniae were also impaired in alveolar macrophages (AMs) from LysM-LepRb-KO mice in vitro and were associated with reduced LTB and enhanced PGE synthesis in vitro. Pretreatment of AMs with LTB and the cyclooxygenase inhibitor, indomethacin, restored phagocytosis but not bacterial killing in vitro. These results confirm our previous observations in leptin-deficient ( ob/ob) and fasted mice and demonstrate that decreased leptin action, as opposed to metabolic irregularities associated with obesity or starvation, is responsible for the defective host defense against pneumococcal pneumonia. They also provide novel targets for therapeutic intervention in humans with bacterial pneumonia.

Leptin signaling impairs macrophage defenses against Salmonella Typhimurium

“…Dock 7m also regulates the actin cytoskeleton, which is critical for phagosome maturation (36, 37). Mancuso et al (38) recently showed using leptin-receptor-deficient alveolar macrophages that leptin positively regulates Streptococcus pneumoniae clearance. This finding is consistent with the differential leptin response we observed between Gram-positive and Gram-negative bacteria.…”

Pancreatic Macrophages: Critical Players in Obesity-Promoted Pancreatic Cancer

“…Conversely, macrophage phagocytosis was impaired in leptin-deficient ob/ob mice [116]. Similarly, in leptin receptor-deficient db/db mice, peritoneal and alveolar macrophages showed defective phagocytosis and were skewed towards M2 polarization [117,118]. Collectively, the available data convincingly suggest that leptin can stimulate pro-inflammatory cytokine production in macrophages, hence potentially contributing to the acceleration of PDAC development by acting on pancreatic macrophages to drive ADM and early PanIN formation/transition in the context of obesity with accompanied hyperleptinemia.…”

The Role of the Adipokine Leptin in Immune Cell Function in Health and Disease

“…Obese Zucker (fa/fa) rats with a leptin receptor mutation, had reduced ability to clear the fungal infection Candida albicans in vivo, as measured by colonyforming units in lung, liver, spleen, heart, and kidney (75). Furthermore, mice with macrophage-specific deletion of the leptin receptor had impaired clearance of Streptococcus pneumoniae in the lungs and spleen (40). The same macrophage specific leptin receptor knockout mice also had elevated pulmonary IL-13 and TNF compared to WT mice 48 h after infection with S. pneumoniae (40).…”

“…Furthermore, mice with macrophage-specific deletion of the leptin receptor had impaired clearance of Streptococcus pneumoniae in the lungs and spleen (40). The same macrophage specific leptin receptor knockout mice also had elevated pulmonary IL-13 and TNF compared to WT mice 48 h after infection with S. pneumoniae (40). Complementary in vitro studies of alveolar macrophages from macrophage specific leptin receptor knockout mice likewise showed decreased macrophage killing and phagocytosis (40).…”