The microbiota contributes to shaping efficient and safe immune defenses in the gut. However, little is known about the role of the microbiota in the education of pulmonary innate immune responses. Here, we tested whether the endogenous microbiota can modulate reactivity of pulmonary tissue to pathogen stimuli by comparing the response of specific pathogen-free (SPF) and germ-free (GF) mice. Using SPF and GF mice intranasally exposed to lipopolysaccharide (LPS), a component of Gram-negative bacteria, we observed earlier and greater inflammation in the pulmonary compartment of GF mice than that of SPF mice. Toll-like receptor 4 (TLR4) was more abundantly expressed in the lungs of GF mice than those of SPF mice at steady state, which could predispose the innate immunity of GF mice to strongly react to environmental stimuli. Lung explants were stimulated with different TLR agonists or infected with the human airways pathogen, respiratory syncytial virus (RSV), resulting in greater inflammation under almost all conditions for the GF explants. Finally, alveolar macrophages (AM) from GF mice presented a higher innate immune response upon RSV infection than those of SPF mice. Overall, these data suggest that the presence of microbiota in SPF mice induced a process of innate immune tolerance in the lungs by a mechanism which remains to be elucidated. Our study represents a step forward to establishing the link between the microbiota and the immune reactivity of the lungs.

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微生物群在肺部免疫成分与先天配体的反应性中起关键作用

微生物群有助于在肠道中形成有效和安全的免疫防御。然而，关于微生物群在肺部先天免疫应答教育中的作用知之甚少。在这里，我们通过比较特定的无病原体（SPF）和无病菌（GF）小鼠的反应，测试了内源性微生物群是否可以调节肺组织对病原体刺激的反应性。使用鼻内暴露于脂多糖（LPS）（革兰氏阴性细菌的一种成分）的SPF和GF小鼠，我们观察到GF小鼠的肺部腔室比SPF小鼠更早且发炎更大。稳定状态下，Toll样受体4（TLR4）在SP小鼠的肺中比在SPF小鼠的肺中更丰富地表达，这可能使GF小鼠的先天免疫力强烈响应环境刺激。用不同的TLR激动剂刺激肺外植体，或感染人气道病原体呼吸道合胞病毒（RSV），在几乎所有条件下，GF外植体都会导致更大的炎症。最后，来自GF小鼠的肺泡巨噬细胞（AM）在RSV感染后表现出比SPF小鼠更高的先天免疫应答。总体而言，这些数据表明，SPF小鼠中微生物群的存在通过尚待阐明的机制诱导了肺中先天免疫耐受的过程。我们的研究代表了建立微生物群与肺部免疫反应性之间联系的一步。GF小鼠的肺泡巨噬细胞（AM）在RSV感染后表现出比SPF小鼠更高的先天免疫应答。总体而言，这些数据表明，SPF小鼠中微生物群的存在通过尚待阐明的机制诱导了肺中先天免疫耐受的过程。我们的研究代表了建立微生物群与肺部免疫反应性之间联系的一步。GF小鼠的肺泡巨噬细胞（AM）在RSV感染后表现出比SPF小鼠更高的先天免疫应答。总体而言，这些数据表明，SPF小鼠中微生物群的存在通过尚待阐明的机制诱导了肺中先天免疫耐受的过程。我们的研究代表了建立微生物群与肺部免疫反应性之间联系的一步。