Pulmonary Center, Boston University School of Medicine, Boston, MA 02118, USA.
J Immunol. 2012 Sep 1;189(5):2450-9. doi: 10.4049/jimmunol.1200634. Epub 2012 Jul 27.
Pneumonia results from bacteria in the alveoli. The alveolar epithelium consists of type II cells, which secrete surfactant and associated proteins, and type I cells, which constitute 95% of the surface area and meet anatomic and structural needs. Other than constitutively expressed surfactant proteins, it is unknown whether alveolar epithelial cells have distinct roles in innate immunity. Because innate immunity gene induction depends on NF-κB RelA (also known as p65) during pneumonia, we generated a murine model of RelA mutated throughout the alveolar epithelium. In response to LPS, only 2 of 84 cytokine transcripts (CCL20 and CXCL5) were blunted in lungs of mutants, suggesting that a very limited subset of immune mediators is selectively elaborated by the alveolar epithelium. Lung CCL20 induction required epithelial RelA regardless of stimulus, whereas lung CXCL5 expression depended on RelA after instillation of LPS but not pneumococcus. RelA knockdown in vitro suggested that CXCL5 induction required RelA in type II cells but not type I cells. Sorted cell populations from mouse lungs revealed that CXCL5 was induced during pneumonia in type I cells, which did not require RelA. TLR2 and STING were also induced in type I cells, with RelA essential for TLR2 but not STING. To our knowledge, these data are the first direct demonstration that type I cells, which constitute the majority of the alveolar surface, mount innate immune responses during bacterial infection. These are also, to our knowledge, the first evidence for entirely RelA-independent pathways of innate immunity gene induction in any cell during pneumonia.
肺炎是由肺泡中的细菌引起的。肺泡上皮由 II 型细胞组成，这些细胞分泌表面活性剂和相关蛋白，以及 I 型细胞，它们构成了 95%的表面积，并满足解剖和结构需求。除了组成型表达的表面活性剂蛋白外，尚不清楚肺泡上皮细胞在先天免疫中是否具有独特的作用。由于先天免疫基因诱导依赖于肺炎期间 NF-κB RelA（也称为 p65），我们生成了一个 RelA 突变整个肺泡上皮的小鼠模型。对 LPS 的反应中，突变体肺部的 84 个细胞因子转录本中只有 2 个（CCL20 和 CXCL5）受到抑制，这表明只有非常有限的免疫介质子集被肺泡上皮选择性地表达。肺 CCL20 的诱导需要上皮细胞 RelA，而与刺激物无关，而肺 CXCL5 的表达取决于 LPS 滴注后的 RelA，但不取决于肺炎球菌。体外 RelA 敲低表明，CXCL5 的诱导需要 II 型细胞中的 RelA，但不需要 I 型细胞。从小鼠肺部分离的细胞群表明，I 型细胞在肺炎期间诱导了 CXCL5，而不需要 RelA。TLR2 和 STING 也在 I 型细胞中被诱导，而 RelA 对 TLR2 是必需的，但对 STING 则不是必需的。据我们所知，这些数据是第一个直接证明在细菌感染期间，构成肺泡表面大部分的 I 型细胞会引发先天免疫反应的证据。据我们所知，这些也是在肺炎期间，任何细胞中先天免疫基因诱导的完全不依赖于 RelA 的途径的第一个证据。
