METHODS: Swiss and C57BL/6 (Wild type) and P2X7R-/- were randomized in two groups: control (uninfected) and Schistosoma mansoni-infected. Alternatively, control Swiss and S. mansoni-infected mice were also infected with L. amazonensis.
RESULTS: The pre-treatment of macrophages with the P2X7R antagonist (A74003) or TGF-β reduced the phagocytosis index, mimicking the phenotype of cells from S. mansoni-infected mice and P2X7R-/- mice. Apyrase also reduced the phagocytosis index corroborating the role of ATP to macrophage activation. Moreover, l-arginine-nitric oxide pathway was compromised, which could explain the reduced killing capacity in response to ATP in vitro and in vivo. We found an increased extracellular nucleotide (ATP, ADP and AMP) hydrolysis along with an increased frequency of F4/80+ CD39+ macrophages from the S. mansoni-infected group. Moreover, the content of adenosine in the cell supernatant was higher in the S. mansoni-infected group in relation to controls. Schistosomiasis also increased the expression of macrophage adenosine A2BR. In good accordance, both ADA and the selective A2BR antagonist restored the phagocytosis index of macrophages from S. mansoni-infected group.
CONCLUSIONS: Altogether, the altered P2X7R and A2BR signaling limits the role of macrophages to host defense against L. amazonensis during schistosomiasis, potentially contributing to the pathophysiology and clinically relevant co-infections.
方法:Swiss和C57BL/6(野生型)和P2X7R-/-随机分为两组:对照组(未感染)和曼氏血吸虫感染。或者,对照Swiss和S.mansoni感染的小鼠也感染了amazonensis。
结果:用P2X7R拮抗剂(A74003)或TGF-β预处理巨噬细胞可降低吞噬作用指数,模拟来自S.mansoni感染的小鼠和P2X7R-/-小鼠的细胞的表型。腺苷三磷酸双磷酸酶还降低了吞噬指数,证实了ATP对巨噬细胞活化的作用。此外,L-精氨酸-一氧化氮通路受损,这可以解释体外和体内响应ATP的杀伤能力降低。我们发现细胞外核苷酸(ATP,ADP和AMP)水解以及来自曼氏链球菌感染组的F4/80CD39巨噬细胞的频率增加。此外,与对照组相比,曼氏链球菌感染组的细胞上清液中腺苷含量较高.血吸虫病也增长了巨噬细胞腺苷A2BR的表达。根据好,ADA和选择性A2BR拮抗剂均恢复了曼氏链球菌感染组巨噬细胞的吞噬指数。
结论:总而言之,改变的P2X7R和A2BR信号限制了巨噬细胞在血吸虫病期间宿主防御亚马逊乳杆菌的作用,可能导致病理生理学和临床相关的共感染。