Myeloid ATG16L1 Facilitates Host-Bacteria Interactions in Maintaining Intestinal Homeostasis.
Myeloid ATG16L1 Facilitates Host-Bacteria Interactions in Maintaining Intestinal Homeostasis.
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DOI：
10.4049/jimmunol.1601293
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发表时间：
2017-03-01
期刊：
影响因子：
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通讯作者：
Shih DQ
中科院分区：
文献类型：
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作者：
Zhang H;Zheng L;McGovern DP;Hamill AM;Ichikawa R;Kanazawa Y;Luu J;Kumagai K;Cilluffo M;Fukata M;Targan SR;Underhill DM;Zhang X;Shih DQ
完整的ATG16L1在潘氏细胞功能和肠道内环境稳定中起着重要作用。然而，ATG16L1缺乏在髓系细胞，特别是巨噬细胞中的功能后果还没有完全确定。我们建立了髓系和树突状细胞Atg16l1缺乏的小鼠，并显示髓系Atg16l1缺乏的小鼠在两种急性和一种慢性结肠炎模型中加重了结肠炎，表现为促炎和抗炎巨噬细胞比率增加，促炎细胞因子的产生和IgA包裹的肠道微生物的数量增加。用原代小鼠巨噬细胞进行的机制分析表明，Atg16l1缺乏导致活性氧产生增加，丝裂原吞噬功能受损，微生物杀灭减少，MHCII抗原的加工受损，细胞内运输改变到溶酶体隔间。在ATg16l1缺乏的小鼠原代中性粒细胞中也观察到了活性氧类的增加和微生物杀灭的减少，这可能是髓系室的一般特征。自噬基因ATG16L1的错义多态(Thr300Ala)与克罗恩病(CD)相关。先前的研究表明，这种多态导致ATG16L1 T300A蛋白的切割增强，从而减少自噬。在对照组和携带Atg16l1 T300A风险变异的CD患者群体中的原代人类巨噬细胞中也发现了类似的发现，并对NOD2 CD相关变异进行了对照。这项研究揭示了ATG16L1缺乏导致巨噬细胞功能改变，从而导致CD的严重程度。
Intact ATG16L1 plays an essential role in Paneth cell function and intestinal homeostasis. However, the functional consequences of ATG16L1 deficiency in myeloid cells, particularly macrophages, are not fully characterized. We generated mice with Atg16l1 deficiency in myeloid and dendritic cells and showed mice with myeloid Atg16l1 deficiency had exacerbated colitis in two acute and one chronic model of colitis with increased proinflammatory to anti-inflammatory macrophage ratios, production of proinflammatory cytokines, and numbers of IgA-coated intestinal microbes. Mechanistic analyses using primary murine macrophages showed that Atg16l1 deficiency led to increased reactive oxygen species production, impaired mitophagy, reduced microbial killing, impaired processing of MHCII antigens, and altered intracellular trafficking to the lysosomal compartments. Increased production of reactive oxygen species and reduced microbial killing may be general features of the myeloid compartment as they were also observed in Atg16l1 deficient primary murine neutrophils. A missense polymorphism (Thr300Ala) in the essential autophagy gene ATG16L1 is associated with Crohn’s disease (CD). Previous studies showed that this polymorphism leads to enhanced cleavage of ATG16L1 T300A protein and thus reduced autophagy. Similar findings were shown in primary human macrophages from controls and a population of CD patients carrying the Atg16l1 T300A risk variant and who were controlled for NOD2 CD-associated variants. This study revealed that ATG16L1 deficiency led to alterations in macrophage function that contribute to the severity of CD.