Helminth 2-Cys peroxiredoxin drives Th2 responses through a mechanism involving alternatively activated macrophages
Helminth 2-Cys peroxiredoxin drives Th2 responses through a mechanism involving alternatively activated macrophages
复制标题
DOI：
10.1096/fj.08-106278
复制
发表时间：
2008-11-01
期刊：
影响因子：
4.8
通讯作者：
Dalton, John P.
中科院分区：
文献类型：
--
作者：
Donnelly, Sheila;Stack, Colin M.;Dalton, John P.
在蠕虫感染期间，交替激活的巨噬细胞(AAMacs)是促进Th2反应和抑制Th1驱动的炎症病理的关键。Th2细胞因子IL-4和/或IL-13被认为在AAMACs的诱导和激活中起重要作用。利用由肝片吸虫(Fh)和曼氏血吸虫(Sm)引起的蠕虫感染的小鼠模型，我们证明了一种分泌的抗氧化剂，过氧化还蛋白(PRX)，诱导巨噬细胞交替激活。这些激活的、表达YM1的巨噬细胞促进了初始的CD4(+)T细胞分泌IL-4、IL-5和IL-13。给野生型和IL-4(-/-)和IL-13(-/-)小鼠注射重组FhPrx和SmPrx可诱导AAMacs的产生。此外，Prx在体外可刺激AAMacs标志物(尤其是YM1)的表达，因此其作用不依赖于IL-4/IL-13信号。Prx的免疫调节作用不是由于其抗氧化活性所致，而是一个活性位点Cys残基被Gly取代的失活重组变异体，也可以诱导AAMacs和Th2反应。用重组Prx免疫小鼠或在感染Fh之前被动转移抗Prx抗体，不仅可以阻止AAMacs的诱导，还可以阻止寄生虫特异性Th2反应的发展。我们认为，Prx激活巨噬细胞是寄生虫诱导Th2反应的第一步，因此是一种新的病原体相关分子模式。-Donnelly，S.，Stack，C.M.，O‘Neill，S.M.，Sayed，A.，Williams，D.L.，Dalton，J.P.蠕虫2-Cys Peroxiredosin通过一种交替激活巨噬细胞的机制驱动Th2反应。FASE B J.22,4022-4032(2008)
During helminth infections, alternatively activated macrophages (AAMacs) are key to promoting Th2 responses and suppressing Th1-driven inflammatory pathology. Th2 cytokines IL-4 and/or IL-13 are believed to be important in the induction and activation of AAMacs. Using murine models for the helminth infections caused by Fasciola hepatica (Fh) and Schistosoma mansoni (Sm), we show that a secreted antioxidant, peroxiredoxin (Prx), induces alternative activation of macrophages. These activated, Ym1-expressing macrophages enhanced the secretion of IL-4, IL-5, and IL-13 from naive CD4(+) T cells. Administration of recombinant FhPrx and SmPrx to wild-type and IL-4(-/-) and IL-13(-/-) mice induced the production of AAMacs. In addition, Prx stimulated the expression of markers of AAMacs (particularly, Ym1) in vitro, and therefore can act independently of IL-4/IL-13 signaling. The immunomodulatory property of Prx is not due to its antioxidant activity, as an inactive recombinant variant with active site Cys residues replaced by Gly could also induce AAMacs and Th2 responses. Immunization of mice with recombinant Prx or passive transfer of anti-Prx antibodies prior to infection with Fh not only blocked the induction of AAMacs but also the development of parasite-specific Th2 responses. We propose that Prx activates macrophages as an initial step in the induction of Th2 responses by helminth parasites and is thereby a novel pathogen-associated molecular pattern.-Donnelly, S., Stack, C. M., O'Neill, S. M., Sayed, A. A., Williams, D. L., Dalton, J. P. Helminth 2-Cys peroxiredoxin drives Th2 responses through a mechanism involving alternatively activated macrophages. FASEB J. 22, 4022-4032 (2008)