Transient Receptor Potential Melastatin 2 Regulates Phagosome Maturation and Is Required for Bacterial Clearance in Escherichia coli Sepsis

吞噬体 瞬时受体电位通道 TRPM2型 内体 离子霉素 微生物学 大肠杆菌 败血症 细胞内 医学 生物 免疫学 细胞生物学 受体 吞噬作用 生物化学 基因
作者
Zhanqin Zhang,Ping Cui,Kai Zhang,Qixing Chen,Xiangming Fang
出处
期刊:Anesthesiology [Ovid Technologies (Wolters Kluwer)]
卷期号:126 (1): 128-139 被引量:27
标识
DOI:10.1097/aln.0000000000001430
摘要

Abstract Background Transient receptor potential melastatin 2 is a Ca2+-permeable cation channel abundantly expressed in macrophages. Trpm2−/− mice showed exacerbated infection and mortality during polymicrobial sepsis, which is associated with inefficient bacterial killing in macrophages. However, the mechanism of transient receptor potential melastatin 2 regulating bacterial killing remains unknown. Methods Trpm2 −/− mice were intraperitoneally injected with Escherichia coli. The survival rate (n = 21) and bacterial burden (n = 5) were assessed. The processes of phagosome maturation and phagosome–lysosome fusion in peritoneal macrophages were extensively studied. The impact of increasing intracellular Ca2+ concentration on bacterial clearance in macrophages (n = 3) and on survival rate of Trpm2−/− mice infected with E. coli (n = 21) was investigated. Results Trpm2 −/− mice exhibited increased mortality (85% vs. 54%; P < 0.01) and aggravated bacterial burden during E. coli sepsis. Trpm2−/− peritoneal macrophages infected with E. coli showed dampened recruitment of lysosomal-associated membrane protein 1 and impaired phagosome maturation evidenced by a decrease in the accumulation of early endosome antigen 1, whereas a normal acquisition of Ras-related protein in brain 5. Increasing the cytosolic Ca2+ concentration in Trpm2−/− peritoneal macrophages via ionomycin treatment facilitated early endosome antigen 1 recruitment to Ras-related protein in brain 5 and phagosomal localization of lysosomal-associated membrane protein 1 and consequently enhanced bactericidal activity. Adoptive transfer of ionomycin-treated Trpm2−/− peritoneal macrophages improved bacterial clearance and survival (67% vs. 29%; P < 0.01) in Trpm2−/− mice challenged with E. coli. Conclusions Transient receptor potential melastatin 2 plays a critical role in host defense against invading bacteria via promoting phagosome maturation through facilitation of early endosome antigen 1 recruitment.

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