Phagosomal Acidification Prevents Macrophage Inflammatory Cytokine Production to Malaria, and Dendritic Cells Are the Major Source at the Early Stages of Infection
Phagosomal Acidification Prevents Macrophage Inflammatory Cytokine Production to Malaria, and Dendritic Cells Are the Major Source at the Early Stages of Infection
复制标题
吞噬体酸化阻止巨噬细胞产生疟疾炎症细胞因子，树突状细胞是感染早期的主要来源
DOI：
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发表时间：
2015
影响因子：
4.8
通讯作者：
D. Gowda
中科院分区：
文献类型：
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作者：
Xianzhu Wu;N. Gowda;D. Gowda
背景：巨噬细胞和树突状细胞对疟疾的炎症反应仍然不明确，尽管它们在控制感染、发病机制和保护性免疫发展中起着至关重要的作用。结果：树突状细胞对寄生虫产生炎性细胞因子，而巨噬细胞不产生。结论：快速酸化阻碍了内体受体介导的寄生虫识别和巨噬细胞的细胞因子反应。意义：阻断内体酸化可提高全虫疫苗的效力。在疟疾感染的早期阶段产生的炎性细胞因子有助于形成保护性免疫和病理生理学。为了深入了解这些过程的机制，了解细胞因子的细胞起源是很重要的，因为细胞因子输入和细胞因子产生细胞都起着关键作用。在这里，我们检测了单核细胞、巨噬细胞和树突状细胞（dc）对纯化的恶性疟原虫和伯氏疟原虫ANKA的细胞因子反应，以及来自约利疟原虫17nxl感染和伯氏疟原虫ANKA感染小鼠的脾脏巨噬细胞和dc的细胞因子反应。结果表明，单核细胞和巨噬细胞不向疟疾寄生虫产生炎性细胞因子，DC是感染早期的主要来源，DC亚群产生细胞因子的差异。重要的是，通过抑制液泡型H+- atp酶来阻断吞噬体酸化，使巨噬细胞能够引发细胞因子反应。由于细胞因子对疟原虫的反应主要是通过内体toll样受体介导的，我们的数据表明巨噬细胞无法产生细胞因子是由于吞噬体酸化破坏了内体配体受体的结合。巨噬细胞在内化寄生虫和热杀灭大肠杆菌的同时，有效地向LPS产生细胞因子，表明吞噬体酸化影响内体受体介导的对toll样受体激动剂的识别，而不是细胞表面受体介导的识别。通过阻断内体酸化使单核/巨噬细胞引发对寄生虫的免疫反应可能是有效发展疟疾保护性免疫的一种新策略。这一结果对于提高全寄生虫疟疾疫苗的效力以及设计主要通过内体受体诱导免疫应答的针对病原体的保护性免疫的发展策略具有重要意义。
Background: Macrophage and dendritic cell inflammatory responses to malaria remain undefined despite their crucial roles in controlling infections, pathogenesis, and protective immunity development. Results: Dendritic cells but not macrophages produce inflammatory cytokines to parasites. Conclusion: Rapid acidification prevents endosomal receptor-mediated recognition of parasites and cytokine responses by macrophages. Significance: Blocking endosomal acidification might enhance the efficacy of whole parasite-based vaccine. Inflammatory cytokines produced at the early stages of malaria infection contribute to shaping protective immunity and pathophysiology. To gain mechanistic insight into these processes, it is important to understand the cellular origin of cytokines because both cytokine input and cytokine-producing cells play key roles. Here, we determined cytokine responses by monocytes, macrophages, and dendritic cells (DCs) to purified Plasmodium falciparum and Plasmodium berghei ANKA, and by spleen macrophages and DCs from Plasmodium yoelii 17NXL-infected and P. berghei ANKA-infected mice. The results demonstrate that monocytes and macrophages do not produce inflammatory cytokines to malaria parasites and that DCs are the primary source early in infection, and DC subsets differentially produce cytokines. Importantly, blocking of phagosomal acidification by inhibiting vacuolar-type H+-ATPase enabled macrophages to elicit cytokine responses. Because cytokine responses to malaria parasites are mediated primarily through endosomal Toll-like receptors, our data indicate that the inability of macrophages to produce cytokines is due to the phagosomal acidification that disrupts endosomal ligand-receptor engagement. Macrophages efficiently produced cytokines to LPS upon simultaneously internalizing parasites and to heat-killed Escherichia coli, demonstrating that phagosomal acidification affects endosomal receptor-mediated, but not cell surface receptor-mediated, recognition of Toll-like receptor agonists. Enabling monocytes/macrophages to elicit immune responses to parasites by blocking endosomal acidification can be a novel strategy for the effective development of protective immunity to malaria. The results have important implications for enhancing the efficacy of a whole parasite-based malaria vaccine and for designing strategies for the development of protective immunity to pathogens that induce immune responses primarily through endosomal receptors.
影响因子：
32.4
作者：
Sharma S;DeOliveira RB;Kalantari P;Parroche P;Goutagny N;Jiang Z;Chan J;Bartholomeu DC;Lauw F;Hall JP;Barber GN;Gazzinelli RT;Fitzgerald KA;Golenbock DT
通讯作者：
Golenbock DT
影响因子：
32.4
作者：
Hashimoto D;Miller J;Merad M
通讯作者：
Merad M