Chiba Norika, Shimada Kenichi, Chen Shuang, Jones Heather D, Alsabeh Randa, Slepenkin Anatoly V, Peterson Ellena, Crother Timothy R, Arditi Moshe
Division of Pediatric Infectious Diseases and Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center and David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90048;
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center and David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90048;
J Immunol. 2015 Apr 15;194(8):3840-51. doi: 10.4049/jimmunol.1402685. Epub 2015 Mar 9.
Mast cells are known as central players in allergy and anaphylaxis, and they play a pivotal role in host defense against certain pathogens. Chlamydia pneumoniae is an important human pathogen, but it is unclear what role mast cells play during C. pneumoniae infection. We infected C57BL/6 (wild-type [WT]) and mast cell-deficient mice (Kit(W-sh/W-sh) [Wsh]) with C. pneumoniae. Wsh mice showed improved survival compared with WT mice, with fewer cells in Wsh bronchoalveolar lavage fluid (BALF), despite similar levels of cytokines and chemokines. We also found a more rapid clearance of bacteria from the lungs of Wsh mice compared with WT mice. Cromolyn, a mast cell stabilizer, reduced BALF cells and bacterial burden similar to the levels seen in Wsh mice; conversely, Compound 48/80, a mast cell degranulator, increased the number of BALF cells and bacterial burden. Histology showed that WT lungs had diffuse inflammation, whereas Wsh mice had patchy accumulations of neutrophils and perivascular accumulations of lymphocytes. Infected Wsh mice had reduced amounts of matrix metalloprotease-9 in BALF and were resistant to epithelial integral membrane protein degradation, suggesting that barrier integrity remains intact in Wsh mice. Mast cell reconstitution in Wsh mice led to enhanced bacterial growth and normal epithelial integral membrane protein degradation, highlighting the specific role of mast cells in this model. These data suggest that mast cells play a detrimental role during C. pneumoniae infection by facilitating immune cell infiltration into the airspace and providing a more favorable replicative environment for C. pneumoniae.
肥大细胞被认为是过敏和过敏反应的核心参与者,并且在宿主抵御某些病原体的过程中发挥关键作用。肺炎衣原体是一种重要的人类病原体,但尚不清楚肥大细胞在肺炎衣原体感染过程中发挥何种作用。我们用肺炎衣原体感染了C57BL/6(野生型[WT])小鼠和肥大细胞缺陷小鼠(Kit(W-sh/W-sh)[Wsh])。与WT小鼠相比,Wsh小鼠的存活率提高,其支气管肺泡灌洗液(BALF)中的细胞数量更少,尽管细胞因子和趋化因子水平相似。我们还发现,与WT小鼠相比,Wsh小鼠肺部细菌的清除速度更快。肥大细胞稳定剂色甘酸钠降低了BALF细胞数量和细菌负荷,其水平与Wsh小鼠相似;相反,肥大细胞脱颗粒剂化合物48/80增加了BALF细胞数量和细菌负荷。组织学检查显示,WT小鼠肺部有弥漫性炎症,而Wsh小鼠有中性粒细胞的斑片状聚集和血管周围淋巴细胞聚集。感染的Wsh小鼠BALF中基质金属蛋白酶-9的含量减少,并且对上皮整合膜蛋白降解具有抗性,这表明Wsh小鼠的屏障完整性保持完好。Wsh小鼠中的肥大细胞重建导致细菌生长增强和上皮整合膜蛋白正常降解,突出了肥大细胞在该模型中的特定作用。这些数据表明,肥大细胞在肺炎衣原体感染过程中通过促进免疫细胞浸润到气腔中并为肺炎衣原体提供更有利的复制环境而发挥有害作用。