Association of Myeloid Liver Kinase B1 Depletion 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 Stk11(fl/fl)) or neutrophils (Mrp8-cre x Stk11(fl/fl)) were infected with Klebsiella pneumoniae via the airways. LysM-cre x Stk11(fl/fl) mice were also intranasally challenged with lipopolysaccharide (LPS). Results Mice with myeloid LKB1 deficiency, but not those with neutrophil LKB1 deficiency, had increased bacterial loads in lungs 6-40 hours after infection, compared with control mice, pointing to a role for LKB1 in macrophages. Myeloid LKB1 deficiency was associated with reduced cytokine release into the airways on local LPS instillation. The number of classic (SiglecF(high)CD11b(neg)) 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, these mice had AMs with a nonclassic (SiglecF(low)CD11b(pos)) phenotype. AMs did not up-regulate 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. Myeloid liver kinase B1 (LKB1) depletion reduces alveolar macrophages and impairs host defense against Klebsiella pneumoniae in the lung. LKB1 deficiency in alveolar macrophages does not affect glucose metabolism or immune functions, such as tumor necrosis factor production or phagocytosis.

Automated summary

This study found that myeloid LKB1 plays an important role in maintaining an adequate number of alveolar macrophages (AMs) during pneumonia, while LKB1 deficiency in neutrophils has no effect. These findings reveal the mechanism of LKB1's role in innate immunity in the lungs.