Targeting the Annexin A1-FPR2/ALX pathway for host-directed therapy in dengue disease.
Targeting the Annexin A1-FPR2/ALX pathway for host-directed therapy in dengue disease.
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DOI：
10.7554/elife.73853
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发表时间：
2022-03-16
期刊：
影响因子：
7.7
通讯作者：
Teixeira MM
中科院分区：
文献类型：
--
作者：
Costa VV;Sugimoto MA;Hubner J;Bonilha CS;Queiroz-Junior CM;Gonçalves-Pereira MH;Chen J;Gobbetti T;Libanio Rodrigues GO;Bambirra JL;Passos IB;Machado Lopes CE;Moreira TP;Bonjour K;Melo RCN;Oliveira MAP;Andrade MVM;Sousa LP;Souza DG;Santiago HDC;Perretti M;Teixeira MM
宿主免疫应答有助于登革热的发病机制和严重程度，但内源性炎症解决途径的失败可能导致疾病的可能性尚未考虑。已知促分解蛋白膜联蛋白A1（AnxA 1）可以平衡过度炎症和肥大细胞（MC）活化。我们假设AnxA 1参与不足是登革热相关的细胞因子风暴和血管病变的基础。检测了登革热患者和感染小鼠血浆中的AnxA 1水平。免疫活性的干扰素（α和β）受体1敲除（KO）、AnxA 1 KO和甲酰肽受体2（FPR 2）KO小鼠用登革病毒（DENV）感染并用AnxA 1模拟肽Ac 2 -26处理以进行分析。此外，在体外和体内评估了Ac 2 -26对DENV诱导的MC脱粒的作用。我们观察到AnxA 1的循环水平在登革热患者和DENV感染的小鼠中降低。虽然缺乏AnxA 1或其受体FPR 2会加重感染小鼠的疾病，但用AnxA 1激动性肽治疗可减轻疾病表现，减轻疾病症状。两种临床结果均归因于DENV介导的病毒载量非依赖性MC脱粒的调节。因此，我们已经确定，改变水平的促消退介质AnxA 1在DENV感染中具有病理相关性，表明FPR 2/ALX激动剂作为登革热疾病的治疗靶点。
Host immune responses contribute to dengue’s pathogenesis and severity, yet the possibility that failure in endogenous inflammation resolution pathways could characterise the disease has not been contemplated. The pro-resolving protein Annexin A1 (AnxA1) is known to counterbalance overexuberant inflammation and mast cell (MC) activation. We hypothesised that inadequate AnxA1 engagement underlies the cytokine storm and vascular pathologies associated with dengue disease. Levels of AnxA1 were examined in the plasma of dengue patients and infected mice. Immunocompetent, interferon (alpha and beta) receptor one knockout (KO), AnxA1 KO, and formyl peptide receptor 2 (FPR2) KO mice were infected with dengue virus (DENV) and treated with the AnxA1 mimetic peptide Ac2-26 for analysis. In addition, the effect of Ac2-26 on DENV-induced MC degranulation was assessed in vitro and in vivo. We observed that circulating levels of AnxA1 were reduced in dengue patients and DENV-infected mice. Whilst the absence of AnxA1 or its receptor FPR2 aggravated illness in infected mice, treatment with AnxA1 agonistic peptide attenuated disease manifestationsatteanuated the symptoms of the disease. Both clinical outcomes were attributed to modulation of DENV-mediated viral load-independent MC degranulation. We have thereby identified that altered levels of the pro-resolving mediator AnxA1 are of pathological relevance in DENV infection, suggesting FPR2/ALX agonists as a therapeutic target for dengue disease.
影响因子：
7.8
作者：
Combs, J W
通讯作者：
Combs, J W
DOI：
10.1083/jcb.31.3.563
发表时间：
1966-12
期刊：
The Journal of cell biology
影响因子：
--
作者：
Combs JW
通讯作者：
Combs JW