Reduced Annexin A1 Expression Associates with Disease Severity and Inflammation in Multiple Sclerosis Patients
Reduced Annexin A1 Expression Associates with Disease Severity and Inflammation in Multiple Sclerosis Patients
复制标题
DOI：
10.4049/jimmunol.1801683
复制
发表时间：
2019-10-01
影响因子：
4.4
通讯作者：
De Rosa, Veronica
中科院分区：
文献类型：
--
作者：
Colamatteo, Alessandra;Maggioli, Elisa;De Rosa, Veronica
慢性神经炎症是多发性硬化症（MS）的一个关键病理标志，这表明在疾病中通过专门的前溶解分子对炎症的溶解是失调的。膜联蛋白A1（ANXA 1）是糖皮质激素诱导的蛋白质，其通过包括抑制白细胞募集和活化的几种机制促进炎症的消退。在这项研究中，我们研究了ANXA 1影响复发/缓解型MS（RRMS）中T细胞效应子功能的能力，RRMS是一种由促炎性Th 1/Th 17细胞维持的自身免疫性疾病。初治RRMS受试者中ANXA 1的循环表达水平与疾病评分和进展呈负相关。在细胞水平，RRMS受试者的CD 4（+）CD 25（-）常规T细胞和CD 4（+）ROR γ t（+）T（Th 17）细胞产生ANXA 1受损，这与体外血脑屏障模型中迁移能力增加有关。从机制上讲，ANXA 1损害单核细胞成熟继发于STAT 3超活化，并有效降低T细胞活化，增殖和糖酵解。总之，这些发现确定了由ANXA 1表达失调引起的RRMS中受损的疾病解决途径，这些途径可能代表RRMS中新的潜在治疗靶点。
Chronic neuroinflammation is a key pathological hallmark of multiple sclerosis (MS) that suggests that resolution of inflammation by specialized proresolving molecules is dysregulated in the disease. Annexin A1 (ANXA1) is a protein induced by glucocorticoids that facilitates resolution of inflammation through several mechanisms that include an inhibition of leukocyte recruitment and activation. In this study, we investigated the ability of ANXA1 to influence T cell effector function in relapsing/remitting MS (RRMS), an autoimmune disease sustained by proinflammatory Th1/Th17 cells. Circulating expression levels of ANXA1 in naive-to-treatment RRMS subjects inversely correlated with disease score and progression. At the cellular level, there was an impaired ANXA1 production by CD4(+) CD25(-) conventional T and CD4(+) ROR gamma t(+) T (Th17) cells from RRMS subjects that associated with an increased migratory capacity in an in vitro model of blood brain barrier. Mechanistically, ANXA1 impaired monocyte maturation secondarily to STAT3 hyperactivation and potently reduced T cell activation, proliferation, and glycolysis. Together, these findings identify impaired disease resolution pathways in RRMS caused by dysregulated ANXA1 expression that could represent new potential therapeutic targets in RRMS.