Innate-like function of memory Th17 cells for enhancing endotoxin-induced acute lung inflammation through IL-22.
Innate-like function of memory Th17 cells for enhancing endotoxin-induced acute lung inflammation through IL-22.
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DOI：
10.1093/intimm/dxv070
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发表时间：
2016-05
影响因子：
4.4
通讯作者：
Ryota Sakaguchi;S. Chikuma;T. Shichita;R. Morita;T. Sekiya;W. Ouyang;Tomomi Ueda;H. Seki;H. Morisaki;A. Yoshimura
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文献类型：
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作者：
Ryota Sakaguchi;S. Chikuma;T. Shichita;R. Morita;T. Sekiya;W. Ouyang;Tomomi Ueda;H. Seki;H. Morisaki;A. Yoshimura
脂多糖（LPS）诱导的急性肺损伤（ALI）被称为急性呼吸窘迫综合征的小鼠模型；然而，t细胞源性细胞因子在ALI中的作用尚未确定。我们发现，在一个肺中LPS刺激导致先天型促炎细胞因子如IL-6和TNF-α的快速诱导，随后是t细胞型细胞因子的表达，包括IL-17、IL-22和IFN-γ。我们发现IL-23对ALI很重要，因为通过基因破坏或抗il -12/23p40抗体治疗阻断IL-23可减少中性粒细胞浸润和支气管肺泡灌洗液（BALF）中炎症细胞因子的分泌。IL-23主要由F4/80(+)CD11c（+）肺泡巨噬细胞产生，经抗生素预处理后，IL-23的表达明显降低，提示产生IL-23的巨噬细胞的产生需要共生菌。出乎意料的是，在t细胞来源的细胞因子中，IL-22而不是IL-17或IFN-γ在lps诱导的ALI中起主要作用。LPS灌注后，BALF中IL-22蛋白水平高于IL-17， IL-22主要来源于记忆Th17细胞。在没有TCR刺激的情况下，肺记忆CD4(+) T细胞对IL-1β + IL-23的反应可能产生比IL-17更高水平的IL-22。我们的研究揭示了肺记忆细胞Th17的先天功能，该细胞响应IL-23产生IL-22，并参与ALI的夸大。
Lipopolysaccharide (LPS)-induced acute lung injury (ALI) is known as a mouse model of acute respiratory distress syndrome; however, the function of T-cell-derived cytokines in ALI has not yet been established. We found that LPS challenge in one lung resulted in a rapid induction of innate-type pro-inflammatory cytokines such as IL-6 and TNF-α, followed by the expression of T-cell-type cytokines, including IL-17, IL-22 and IFN-γ. We discovered that IL-23 is important for ALI, since blockage of IL-23 by gene disruption or anti-IL-12/23p40 antibody treatment reduced neutrophil infiltration and inflammatory cytokine secretion into the bronchoalveolar lavage fluid (BALF). IL-23 was mostly produced from F4/80(+)CD11c(+) alveolar macrophages, and IL-23 expression was markedly reduced by the pre-treatment of mice with antibiotics, suggesting that the development of IL-23-producing macrophages required commensal bacteria. Unexpectedly, among T-cell-derived cytokines, IL-22 rather than IL-17 or IFN-γ played a major role in LPS-induced ALI. IL-22 protein levels were higher than IL-17 in the BALF after LPS instillation, and the major source of IL-22 was memory Th17 cells. Lung memory CD4(+) T cells had a potential to produce IL-22 at higher levels than IL-17 in response to IL-1β plus IL-23 without TCR stimulation. Our study revealed an innate-like function of the lung memory Th17 cells that produce IL-22 in response to IL-23 and are involved in exaggeration of ALI.