Dectin-3 Deficiency Promotes Colitis Development due to Impaired Antifungal Innate Immune Responses in the Gut.
Dectin-3 Deficiency Promotes Colitis Development due to Impaired Antifungal Innate Immune Responses in the Gut.
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Dectin-3 缺乏会因肠道抗真菌先天免疫反应受损而促进结肠炎的发展
DOI：
10.1371/journal.ppat.1005662
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发表时间：
2016-06
期刊：
影响因子：
6.7
通讯作者：
Lin X
中科院分区：
文献类型：
--
作者：
Wang T;Pan D;Zhou Z;You Y;Jiang C;Zhao X;Lin X
肠道真菌与肠道免疫系统之间的相互作用对建立结肠内稳态至关重要。在这里，我们发现，与野生型小鼠相比，Dectin-3（Clec 4d-/-）（一种感知真菌感染的C型凝集素受体）缺陷的小鼠对葡聚糖硫酸钠（DSS）诱导的结肠炎更敏感。假丝酵母菌（C.）在Clec 4d-/-小鼠中，DSS处理后，补充C. Tropicalis仅在Clec 4d-/-小鼠中加重结肠炎，而在野生型对照中不加重。机制上，Dectin-3缺陷损害巨噬细胞的吞噬和杀真菌能力，并且C.热带假单胞菌诱导的NF-κB活化和细胞因子产生。来自Dectin-3缺陷型巨噬细胞的条件培养基在促进结肠上皮细胞的组织修复方面是有缺陷的。最后，抗真菌疗法在治疗Clec 4d-/-小鼠的结肠炎中是有效的。这些研究确定了Dectin-3的作用及其与肠道真菌的功能相互作用在肠道免疫系统和调节结肠稳态。C型凝集素受体（CLRs）包括作为模式识别受体（PRRs）起作用的可溶性和跨膜蛋白的不同家族。Dectin-3（也称为MCL/CLECSF 8/Clec 4d）是髓样细胞特异性的CD 4家族成员，可以识别细菌和真菌成分并诱导调节免疫应答的细胞内信号传导途径。虽然研究人员已经探索了Dectin-3在全身免疫中的作用，但其在胃肠道免疫系统中的功能尚不清楚。使用葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠模型，我们在这里显示，与野生型小鼠相比，Dectin-3缺陷型小鼠对DSS诱导的结肠炎更易感。研究了一种真菌C.在Dectin-3缺陷型小鼠中，DSS治疗后肠道中的Tropicalis显著增加，并且抗真菌治疗可以有效地保护这些小鼠免受结肠炎。综上所述，我们证明了Dectin-3的重要功能及其与肠道真菌在肠道免疫应答和结肠稳态调节中的功能相互作用。
Interactions between commensal fungi and gut immune system are critical for establishing colonic homeostasis. Here we found that mice deficient in Dectin-3 (Clec4d -/-), a C-type lectin receptor that senses fungal infection, were more susceptible to dextran sodium sulfate (DSS)-induced colitis compared with wild-type mice. The specific fungal burden of Candida (C.) tropicalis was markedly increased in the gut after DSS treatment in Clec4d -/- mice, and supplementation with C. tropicalis aggravated colitis only in Clec4d -/- mice, but not in wild-type controls. Mechanistically, Dectin-3 deficiency impairs phagocytic and fungicidal abilities of macrophages, and C. tropicalis-induced NF-κB activation and cytokine production. The conditioned media derived from Dectin-3-deficient macrophages were defective in promoting tissue repairing in colonic epithelial cells. Finally, anti-fungal therapy was effective in treating colitis in Clec4d -/- mice. These studies identified the role of Dectin-3 and its functional interaction with commensal fungi in intestinal immune system and regulation of colonic homeostasis. C-type lectin receptors (CLRs) comprise a diverse family of soluble and trans-membrane proteins that function as pattern recognition receptors (PRRs). Dectin-3 (also known as MCL/CLECSF8/Clec4d), a myeloid cell-specific CLR family member, could recognize bacterial and fungal components and induce intracellular signaling pathways that regulate the immune response. Although investigators have explored the role of Dectin-3 in systemic immunity, its function in the gastrointestinal immune system is not clear. Using a dextran sodium sulfate (DSS)-induced colitis mice model, we show here Dectin-3-deficient mice were more susceptible to DSS-induced colitis compared with wild-type mice. The specific fungal burden of a commensal fungi C. tropicalis was markedly increased in the gut after DSS treatment in Dectin-3-deficient mice, and antifungal therapy could effectively protect these mice from colitis. Taken together, we demonstrate the important function of Dectin-3 and its functional interaction with commensal fungi in intestinal immune responses and regulation of colonic homeostasis.