通过CB2激活，阿南达胺降低了淋巴细胞对肠道的迁移，并在靶器官降低了TNF-α，从而保护小鼠免受移植物抗宿主病的损害。
Anandamide reduces the migration of lymphocytes to the intestine BY CB2 activation and reduces TNF-α in the target organs, protecting mice from graft-versus-host disease.
发表日期：2023 Aug 01
作者：
Bárbara Betônico Berg, Ana Flávia Santos Linhares, Daniel Messias Martins, Milene Alvarenga Rachid, Stêfany Bruno de Assis Cau, Giovane Galdino de Souza, Jonatan Constança Silva de Carvalho, Carlos Arterio Sorgi, Thiago Roberto Lima Romero, Vanessa Pinho, Mauro Martins Teixeira, Marina Gomes Miranda E Castor
来源：
CLINICAL PHARMACOLOGY & THERAPEUTICS
摘要：
移植物抗宿主病（GVHD）是骨髓移植的一个严重的炎症疾病，通常作为二次并发症出现。目前的治疗方法有效性有限，无法在炎症和移植物抗肿瘤效应之间取得平衡。在本研究中，我们调查了内源性大麻素阿内酰胺对GVHD的复杂病理学的影响。我们评估了不可逆脂肪酸胺酯水解酶抑制剂或外源性阿内酰胺的效果，发现它们增加了GVHD小鼠的生存率，减少了临床症状。在GVHD小鼠的肠道中，外源性阿内酰胺的治疗还导致CD3+、CD3+CD4+和CD3+CD8+细胞数量的减少，从而减少了CD3+CD4+和CD3+CD8+细胞的激活，如通过增强的T细胞共刺激分子CD28的表达进行评估。在GVHD小鼠的肠道中，外源性AEA还能够减少TNF-α的水平，并增加IL-10的含量。在肝脏中，外源性AEA能够减少损伤，降低TNF-α的水平和CD3+CD8+细胞的数量。有趣的是，阿内酰胺减少了Mac-1α的表达，降低了移植细胞在肠系膜静脉中的粘附能力。这些作用被CB2选择性激动剂JWH133所模拟，并被CB2拮抗剂的治疗所废除。此外，阿内酰胺治疗引起的生存效应与CB2受体相关，因为CB2拮抗剂废除了生存效应。本研究显示了CB2受体在通过阿内酰胺治疗对GVHD炎症反应的调节中的关键作用，阿内酰胺是最重要的内源性大麻素。版权所有 © 2023 Elsevier B.V. 发表。
Graft-versus-host disease (GVHD) is a serious inflammatory illness that often occurs as a secondary complication of bone marrow transplantation. Current therapies have limited effectiveness and fail to achieve a balance between inflammation and the graft-versus-tumor effect. In this study, we investigate the effects of the endocannabinoid anandamide on the complex pathology of GVHD. We assess the effects of an irreversible inhibitor of fatty acid amine hydrolase or exogenous anandamide and find that they increase survival and reduce clinical signs in GVHD mice. In the intestine of GVHD mice, treatment with exogenous anandamide also leads to a reduction in the number of CD3+, CD3+CD4+, and CD3+CD8+ cells, which reduces the activation of CD3+CD4+ and CD3+CD8+ cells, as assessed by enhanced CD28 expression, a T cell co-stimulatory molecule. Exogenous AEA was also able to reduce TNF-α and increase IL-10 in the intestine of GVHD mice. In the liver, exogenous AEA reduces injury, TNF-α levels, and the number of CD3+CD8+ cells. Interestingly, anandamide reduces Mac-1α, which lowers the adhesion of transplanted cells in mesenteric veins. These effects are mimicked by JWH133-a CB2 selective agonist-and abolished by treatment with a CB2 antagonist. Furthermore, the effects caused by anandamide treatment on survival were related to the CB2 receptor, as the CB2 antagonist abolished it. This study shows the critical role of the CB2 receptor in the modulation of the inflammatory response of GVHD by treatment with anandamide, the most prominent endocannabinoid.Copyright © 2023. Published by Elsevier B.V.