Phagocytosis-dependent activation of a TLR9-BTK-calcineurin-NFAT pathway co-ordinates innate immunity to Aspergillus fumigatus.
Phagocytosis-dependent activation of a TLR9-BTK-calcineurin-NFAT pathway co-ordinates innate immunity to Aspergillus fumigatus.
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DOI：
10.15252/emmm.201404556
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发表时间：
2015-03
影响因子：
11.1
通讯作者：
Armstrong-James D
中科院分区：
文献类型：
--
作者：
Herbst S;Shah A;Mazon Moya M;Marzola V;Jensen B;Reed A;Birrell MA;Saijo S;Mostowy S;Shaunak S;Armstrong-James D
使用钙调神经磷酸酶抑制剂的移植受者有很高的侵袭性真菌感染风险。了解钙调神经磷酸酶抑制剂如何损害真菌免疫是确定感染风险的关键优先事项。在这里，我们证明了钙调神经磷酸酶抑制剂他克莫司通过抑制巨噬细胞的炎症反应，损害了主要霉菌病原体烟曲霉从呼吸道的清除。这会导致早期有缺陷的中性粒细胞招募和真菌清除。我们在斑马鱼中证实了这些发现，表明在炎症过程中钙调神经磷酸酶信号在中性粒细胞招募中发挥了进化上的保守作用。我们发现CaN-NFAT的激活依赖于吞噬功能，并与NF-κB协同产生肿瘤坏死因子-α。对于酵母酵母多糖颗粒，巨噬细胞钙调神经磷酸酶-NFAT的激活是通过吞噬细胞Dectin-1-脾酪氨酸激酶途径进行的，而对于烟曲霉菌来说，激活是通过吞噬TLR9依赖和Bruton酪氨酸激酶依赖的信号通路发生的，而不是MyD88。我们证实了NFAT和NF-κB在原代肺泡巨噬细胞产生肿瘤坏死因子-α方面的协同作用。这些观察发现，新发现的巨噬细胞TLR9-BTK-Calcineurin-NFAT信号通路的抑制是导致器官移植相关侵袭性曲霉病的关键免疫缺陷。
Transplant recipients on calcineurin inhibitors are at high risk of invasive fungal infection. Understanding how calcineurin inhibitors impair fungal immunity is a key priority for defining risk of infection. Here, we show that the calcineurin inhibitor tacrolimus impairs clearance of the major mould pathogen Aspergillus fumigatus from the airway, by inhibiting macrophage inflammatory responses. This leads to defective early neutrophil recruitment and fungal clearance. We confirm these findings in zebrafish, showing an evolutionarily conserved role for calcineurin signalling in neutrophil recruitment during inflammation. We find that calcineurin–NFAT activation is phagocytosis dependent and collaborates with NF-κB for TNF-α production. For yeast zymosan particles, activation of macrophage calcineurin–NFAT occurs via the phagocytic Dectin-1–spleen tyrosine kinase pathway, but for A. fumigatus, activation occurs via a phagosomal TLR9-dependent and Bruton's tyrosine kinase-dependent signalling pathway that is independent of MyD88. We confirm the collaboration between NFAT and NF-κB for TNF-α production in primary alveolar macrophages. These observations identify inhibition of a newly discovered macrophage TLR9–BTK–calcineurin–NFAT signalling pathway as a key immune defect that leads to organ transplant-related invasive aspergillosis.
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DOI：
10.4049/jimmunol.1300748
发表时间：
2013-09-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Carrion Sde J;Leal SM Jr;Ghannoum MA;Aimanianda V;Latgé JP;Pearlman E
通讯作者：
Pearlman E
影响因子：
4.3
作者：
Herbst S;Shah A;Carby M;Chusney G;Kikkeri N;Dorling A;Bignell E;Shaunak S;Armstrong-James D
通讯作者：
Armstrong-James D
DOI：
10.1523/jneurosci.1064-09.2009
发表时间：
2009-10-14
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Abdul HM;Sama MA;Furman JL;Mathis DM;Beckett TL;Weidner AM;Patel ES;Baig I;Murphy MP;LeVine H 3rd;Kraner SD;Norris CM
通讯作者：
Norris CM
DOI：
10.1086/652768
发表时间：
2010-06-15
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
--
作者：
Baddley JW;Andes DR;Marr KA;Kontoyiannis DP;Alexander BD;Kauffman CA;Oster RA;Anaissie EJ;Walsh TJ;Schuster MG;Wingard JR;Patterson TF;Ito JI;Williams OD;Chiller T;Pappas PG
通讯作者：
Pappas PG
影响因子：
64.8
作者：
Gross, Olaf;Gewies, Andreas;Ruland, Juergen
通讯作者：
Ruland, Juergen