Achouiti Ahmed, de Vos Alex F, van 't Veer Cornelis, Florquin Sandrine, Tanck Michael W, Nawroth Peter P, Bierhaus Angelika, van der Poll Tom, van Zoelen Marieke A D
Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
PLoS One. 2016 Jan 29;11(1):e0141000. doi: 10.1371/journal.pone.0141000. eCollection 2016.
Klebsiella species is the second most commonly isolated gram-negative organism in sepsis and a frequent causative pathogen in pneumonia. The receptor for advanced glycation end products (RAGE) is expressed on different cell types and plays a key role in diverse inflammatory responses. We here aimed to investigate the role of RAGE in the host response to Klebsiella (K.) pneumoniae pneumonia and intransally inoculated rage gene deficient (RAGE-/-) and normal wild-type (Wt) mice with K. pneumoniae. Klebsiella pneumonia resulted in an increased pulmonary expression of RAGE. Furthermore, the high-affinity RAGE ligand high mobility group box-1 was upregulated during K. pneumoniae pneumonia. RAGE deficiency impaired host defense as reflected by a worsened survival, increased bacterial outgrowth and dissemination in RAGE-/- mice. RAGE-/- neutrophils showed a diminished phagocytosing capacity of live K. pneumoniae in vitro. Relative to Wt mice, RAGE-/- mice demonstrated similar lung inflammation, and slightly elevated-if any-cytokine and chemokine levels and unchanged hepatocellular injury. In addition, RAGE-/- mice displayed an unaltered response to intranasally instilled Klebsiella lipopolysaccharide (LPS) with respect to pulmonary cell recruitment and local release of cytokines and chemokines. These data suggest that (endogenous) RAGE protects against K. pneumoniae pneumonia. Also, they demonstrate that RAGE contributes to an effective antibacterial defense during K. pneumoniae pneumonia, at least partly via its participation in the phagocytic properties of professional granulocytes. Additionally, our results indicate that RAGE is not essential for the induction of a local and systemic inflammatory response to either intact Klebsiella or Klebsiella LPS.
克雷伯菌属是脓毒症中第二常见的革兰氏阴性菌，也是肺炎中常见的致病病原体。晚期糖基化终产物受体（RAGE）在不同细胞类型上表达，在多种炎症反应中起关键作用。我们旨在研究RAGE在宿主对肺炎克雷伯菌肺炎的反应中的作用，并将肺炎克雷伯菌经鼻接种到RAGE基因缺陷（RAGE-/-）和正常野生型（Wt）小鼠体内。肺炎克雷伯菌导致肺组织中RAGE表达增加。此外，在肺炎克雷伯菌肺炎期间，高亲和力RAGE配体高迁移率族蛋白B1上调。RAGE缺陷损害宿主防御，表现为RAGE-/-小鼠存活率降低、细菌生长和播散增加。RAGE-/-中性粒细胞在体外对活的肺炎克雷伯菌的吞噬能力减弱。相对于Wt小鼠，RAGE-/-小鼠表现出相似的肺部炎症，细胞因子和趋化因子水平略有升高（如果有的话），肝细胞损伤未改变。此外，RAGE-/-小鼠对经鼻滴注的肺炎克雷伯菌脂多糖（LPS）在肺细胞募集以及细胞因子和趋化因子的局部释放方面的反应未改变。这些数据表明（内源性）RAGE可预防肺炎克雷伯菌肺炎。此外，它们表明RAGE在肺炎克雷伯菌肺炎期间有助于有效的抗菌防御，至少部分是通过其参与专业粒细胞的吞噬特性。此外，我们的结果表明，RAGE对于对完整的肺炎克雷伯菌或肺炎克雷伯菌LPS诱导局部和全身炎症反应并非必不可少。
