CARD9S12N facilitates the production of IL-5 by alveolar macrophages for the induction of type 2 immune responses
CARD9S12N facilitates the production of IL-5 by alveolar macrophages for the induction of type 2 immune responses
复制标题
CARD9(S12N) 促进肺泡巨噬细胞产生 IL-5，以诱导 2 型免疫反应
DOI：
10.1038/s41590-018-0112-4
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发表时间：
2018-06-01
影响因子：
30.5
通讯作者：
Lin, Xin
中科院分区：
文献类型：
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作者：
Xu, Xia;Xu, Jin-Fu;Lin, Xin
衔接子CARD 9在C型凝集素受体（CLR）的下游起作用，用于感测微生物感染，这导致辅助T细胞的T（H）1和T（H）17亚群的应答。人类基因组中CARD 9处的单核苷酸多态性rs 4077515导致取代（S12 N）（CARD 9（S12 N）），与几种自身免疫性疾病相关。然而，CARD 9（S12 N）的功能仍然未知。在这里，我们产生了CARD 9（S12 N）敲入小鼠，并发现CARD 9（S12 N）在参与CLR后促进了2型免疫应答的诱导。从机制上讲，CARD 9（S12 N）介导了CLR诱导的非典型转录因子NF-κ B亚基RelB的激活，这启动了肺泡巨噬细胞中细胞因子IL-5的产生，用于招募嗜酸性粒细胞，以驱动T（H）2细胞介导的过敏反应。我们在过敏性支气管肺曲霉病患者中鉴定了编码S12 N的纯合CARD 9突变，并揭示了这些患者外周血单核细胞中RelB的活化和IL-5的产生。我们的研究提供了遗传和功能证据，证明CARD 9（S12 N）可以将肺泡巨噬细胞转化为IL-5产生细胞，并促进TH 2细胞介导的病理反应。
The adaptor CARD9 functions downstream of C-type lectin receptors (CLRs) for the sensing of microbial infection, which leads to responses by the T(H)1 and T(H)17 subsets of helper T cells. The single-nucleotide polymorphism rs4077515 at CARD9 in the human genome, which results in the substitution(S12N) (CARD9(S12N)), is associated with several autoimmune diseases. However, the function of CARD9(S12N) has remained unknown. Here we generated CARD9(S12N) knock-in mice and found that CARD9(S12N) facilitated the induction of type 2 immune responses after engagement of CLRs. Mechanistically, CARD9(S12N) mediated CLR-induced activation of the non-canonical transcription factor NF-kappa B subunit RelB, which initiated production of the cytokine IL-5 in alveolar macrophages for the recruitment of eosinophils to drive T(H)2 cell-mediated allergic responses. We identified the homozygous CARD9 mutation encoding S12N in patients with allergic bronchopulmonary aspergillosis and revealed activation of RelB and production of IL-5 in peripheral blood mononuclear cells from these patients. Our study provides genetic and functional evidence demonstrating that CARD9(S12N) can turn alveolar macrophages into IL-5-producing cells and facilitates TH2 cell-mediated pathologic responses.