Center for Experimental and Molecular Medicine, Amsterdam University Medical Centers, Amsterdam, the Netherlands.
Amsterdam Infection & Immunity Institute, Amsterdam, the Netherlands.
J Infect Dis. 2022 Apr 1;225(7):1284-1295. doi: 10.1093/infdis/jiaa416.
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.
Mice deficient for LKB1 in myeloid cells (LysM-cre × Stk11fl/fl) or neutrophils (Mrp8-cre × Stk11fl/fl) were infected with Klebsiella pneumoniae via the airways. LysM-cre × Stk11fl/fl mice were also intranasally challenged with lipopolysaccharide (LPS).
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 (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, these mice had AMs with a "nonclassic" (SiglecFlowCD11bpos) phenotype. AMs did not up-regulate glycolysis in response to LPS, irrespective of LKB1 presence.
Myeloid LKB1 is important for local host defense during Klebsiella pneumonia by maintaining adequate AM numbers in the lung.
肝激酶 B1（LKB1）作为一种肿瘤抑制基因（Stk11），在癌症研究中得到了广泛的研究。我们假设髓系 LKB1 在肺炎的固有免疫中发挥作用。
通过气道感染肺炎克雷伯菌，研究髓系细胞（LysM-cre × Stk11fl/fl）或中性粒细胞（Mrp8-cre × Stk11fl/fl）缺乏 LKB1 的小鼠。LysM-cre × Stk11fl/fl 小鼠还通过鼻腔内给予脂多糖（LPS）进行挑战。
与对照小鼠相比，髓系 LKB1 缺乏的小鼠在感染后 6-40 小时肺部细菌负荷增加，而中性粒细胞 LKB1 缺乏的小鼠则没有，这表明 LKB1 在巨噬细胞中发挥作用。髓系 LKB1 缺乏与局部 LPS 滴注后细胞因子释放到气道减少有关。髓系 LKB1 缺乏小鼠肺部的经典（SiglecFhighCD11bneg）肺泡巨噬细胞（AMs）数量减少了约 50%，这不是由于细胞死亡增加或增殖减少所致。相反，这些小鼠的 AMs 具有“非经典”（SiglecFlowCD11bpos）表型。AMs 未响应 LPS 而上调糖酵解，无论 LKB1 是否存在。
髓系 LKB1 通过维持肺部足够的 AM 数量，对肺炎克雷伯菌肺炎期间的局部宿主防御很重要。
