Center for Experimental and Molecular Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, Meibergdreef 9, G2-129, 1105 AZ, Amsterdam, The Netherlands.
Amsterdam Infection & Immunity Institute, Amsterdam, The Netherlands.
Respir Res. 2022 Sep 12;23(1):241. doi: 10.1186/s12931-022-02168-6.
Liver kinase B1 (Lkb1, gene name Stk11) functions as a tumor suppressor in cancer. Myeloid cell Lkb1 potentiates lung inflammation induced by the Gram-negative bacterial cell wall component lipopolysaccharide and in host defense during Gram-negative pneumonia. Here, we sought to investigate the role of myeloid Lkb1 in lung inflammation elicited by the Gram-positive bacterial cell wall component lipoteichoic acid (LTA) and during pneumonia caused by the Gram-positive respiratory pathogen Streptococcus pneumoniae (Spneu).
Alveolar and bone marrow derived macrophages (AMs, BMDMs) harvested from myeloid-specific Lkb1 deficient (Stk11-ΔM) and littermate control mice were stimulated with LTA or Spneu in vitro. Stk11-ΔM and control mice were challenged via the airways with LTA or infected with Spneu in vivo.
Lkb1 deficient AMs and BMDMs produced less tumor necrosis factor (TNF)α upon activation by LTA or Spneu. During LTA-induced lung inflammation, Stk11-ΔM mice had reduced numbers of AMs in the lungs, as well as diminished cytokine release and neutrophil recruitment into the airways. During pneumonia induced by either encapsulated or non-encapsulated Spneu, Stk11-ΔM and control mice had comparable bacterial loads and inflammatory responses in the lung, with the exception of lower TNFα levels in Stk11-ΔM mice after infection with the non-encapsulated strain.
Myeloid Lkb1 contributes to LTA-induced lung inflammation, but is not important for host defense during pneumococcal pneumonia.
肝激酶 B1（Lkb1，基因名称 Stk11）在癌症中作为肿瘤抑制因子发挥作用。髓系细胞 Lkb1 增强革兰氏阴性细菌细胞壁成分脂多糖诱导的肺炎症，并在革兰氏阴性肺炎期间增强宿主防御。在这里，我们试图研究髓系 Lkb1 在革兰氏阳性细菌细胞壁成分脂磷壁酸（LTA）诱导的肺炎症以及由革兰氏阳性呼吸道病原体肺炎链球菌（Spneu）引起的肺炎中的作用。
从髓系特异性 Lkb1 缺失（Stk11-ΔM）和同窝对照小鼠中分离肺泡和骨髓来源的巨噬细胞（AMs、BMDMs），并用 LTA 或 Spneu 在体外刺激。Stk11-ΔM 和对照小鼠通过气道接受 LTA 或体内感染 Spneu 进行挑战。
LTA 或 Spneu 激活时，Lkb1 缺失的 AMs 和 BMDMs 产生的肿瘤坏死因子（TNF）α减少。在 LTA 诱导的肺炎症中，Stk11-ΔM 小鼠肺部的 AM 数量减少，细胞因子释放和中性粒细胞募集到气道减少。在包膜或非包膜 Spneu 诱导的肺炎中，Stk11-ΔM 和对照小鼠肺部的细菌负荷和炎症反应相当，除了非包膜株感染后 Stk11-ΔM 小鼠的 TNFα 水平较低。
髓系 Lkb1 有助于 LTA 诱导的肺炎症，但在肺炎链球菌肺炎期间对宿主防御不重要。
