Myeloid Liver Kinase B1 depletion is associated with a reduction in alveolar macrophage numbers and an impaired host defense during gram-negative pneumonia.

BACKGROUND: Liver kinase B1 (LKB1) has been studied extensively as a tumor suppressor gene (Stk11) in the context of cancer. We hypothesized that myeloid LKB1 plays a role in innate immunity during pneumonia.

METHODS: Mice deficient for LKB1 in myeloid cells (LysM-cre x Stk11fl/fl ) or neutrophils (Mrp8-cre x Stk11fl/fl) were infected with Klebsiellapneumoniae via the airways. LysM-cre x Stk11fl/fl mice were also intranasally challenged with lipopolysaccharide (LPS).

RESULTS: Myeloid, but not neutrophil LKB1 deficient mice had increased bacterial loads in lungs from 6 to 40 hours after infection as compared to control mice, pointing at a role for LKB1 in macrophages. Myeloid LKB1 deficiency was associated with reduced cytokine release into the airways upon local LPS instillation. The number of classical (SiglecFhighCD11bneg) alveolar macrophages (AMs) was reduced by approximately 50% in the lungs of myeloid LKB1 deficient mice, which was not caused by increased cell death or reduced proliferation. Instead, myeloid LKB1 deficient mice had AMs with a 'non-classical' (SiglecFlowCD11bpos) phenotype. AMs did not upregulate glycolysis in response to LPS, irrespective of LKB1 presence.

CONCLUSION: Myeloid LKB1 is important for local host defense during Klebsiella pneumonia by maintaining adequate AM numbers in the lung.