Laboratory of Immunology, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Shido, Sanuki-shi, Kagawa, Japan.
Japan Science and Technology Agency, CREST, Chiyoda-ku, Tokyo, Japan.
Sci Rep. 2016 Nov 29;6:37914. doi: 10.1038/srep37914.
Retinoic acid (RA)-producing CD103 mature dendritic cells (DCs) in mesenteric lymph nodes (MLNs) play crucial roles in gut immunity. GM-CSF and RA contribute to the expression of the RA-producing enzyme ALDH1A2. However, additional signals appeared to be required for inducing ALDH1A2 mature DCs from immature DCs. We found here that TLR ligands (Ls) and immobilized E-cadherin could provide such signals in FLT3-L-generated bone marrow (BM)-derived DCs after treatment with GM-CSF and the RA receptor agonist Am80. The TLR-L-treated DCs produced proinflammatory cytokines unlike normal ALDH1A2 MLN-DCs, whereas the E-cadherin-treated DCs did not. Immobilized VCAM-1 and semaphorin 7 A exerted effects similar to those of E-cadherin. Soluble anti-integrin β1 antibodies or inhibitors of integrin signaling molecules suppressed the effects of these immobilized proteins, whereas immobilized anti-integrin β1 antibodies enhanced the GM-CSF/Am80-induced ALDH1A2 expression without inducing proinflammatory cytokines. Sequential stimulation of splenic pre-DCs with GM-CSF/Am80 and immobilized E-cadherin or anti-integrin β1 antibody also induced differentiation to mature DCs with high ALDH activity. The E-cadherin-treated BM-DCs induced gut-tropic Foxp3 T cells and alleviated DSS-induced colitis, whereas the TLR-L-treated DCs aggravated DSS-induced colitis. The results suggest that integrin β1-mediated signals contribute to the differentiation and maturation of RA-producing anti-inflammatory DCs.
视黄酸（RA）产生的 CD103 成熟树突状细胞（DCs）在肠系膜淋巴结（MLNs）中发挥着关键作用，在肠道免疫中起着关键作用。GM-CSF 和 RA 有助于表达 RA 产生酶 ALDH1A2。然而，似乎需要额外的信号来从未成熟的 DC 诱导 ALDH1A2 成熟 DC。我们在这里发现，TLR 配体（Ls）和固定的 E-钙黏蛋白可以在 GM-CSF 和 RA 受体激动剂 Am80 处理后，为 FLT3-L 生成的骨髓（BM）衍生的 DC 提供这种信号。TLR-L 处理的 DC 产生促炎细胞因子，与正常的 ALDH1A2 MLN-DC 不同，而 E-钙黏蛋白处理的 DC 则不会。固定的 VCAM-1 和 semaphorin 7A 发挥的作用类似于 E-钙黏蛋白。可溶性抗整合素 β1 抗体或整合素信号分子抑制剂抑制了这些固定蛋白的作用，而固定的抗整合素 β1 抗体增强了 GM-CSF/Am80 诱导的 ALDH1A2 表达，而不会诱导促炎细胞因子。用 GM-CSF/Am80 和固定的 E-钙黏蛋白或抗整合素 β1 抗体连续刺激脾前 DC 也诱导向具有高 ALDH 活性的成熟 DC 分化。E-钙黏蛋白处理的 BM-DC 诱导肠道趋向性 Foxp3 T 细胞，并缓解 DSS 诱导的结肠炎，而 TLR-L 处理的 DC 加重 DSS 诱导的结肠炎。结果表明，整合素 β1 介导的信号有助于 RA 产生抗炎性 DC 的分化和成熟。
