IL-4Ralpha-independent expression of mannose receptor and Ym1 by macrophages depends on their IL-10 responsiveness.
IL-4Ralpha-independent expression of mannose receptor and Ym1 by macrophages depends on their IL-10 responsiveness.
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DOI：
10.1371/journal.pntd.0000689
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发表时间：
2010-05-18
影响因子：
3.8
通讯作者：
Brombacher F
中科院分区：
文献类型：
--
作者：
Dewals BG;Marillier RG;Hoving JC;Leeto M;Schwegmann A;Brombacher F
在急性血吸虫病期间，IL-4Rα依赖的反应对于肉芽肿的形成和宿主的生存是必不可少的。此前，我们证明了缺乏巨噬细胞特异性IL-4Rα的小鼠(LysMcreIl4ra−/lox)会出现更高的肝毒性和肠道炎症；而炎症仅限于缺乏T细胞特异性IL-4Rα表达的小鼠的肝脏(iLkercreIl4ra−/lox)。在这项研究中，我们进一步研究了它们在肝脏肉芽肿性炎症中的作用。在感染曼氏血吸虫的LysMcre4ra−/lox肝肉芽肿小鼠中，巨噬细胞、淋巴细胞或粒细胞群的频率和数量以及Th1型/Th2型细胞因子反应与IL4ra−/lox对照组小鼠相似。相反，在严重破坏的肉芽肿中，我们观察到高干扰素-γ和低IL-4、IL-10和IL-13的Th1型反应在−/lox和Il4ra−/−小鼠中发生转变。正如预期的那样，在LysMcreIl4ra−/lox和iLockcreIl4ra−/lox肉芽肿中，交替的巨噬细胞激活减少，精氨酸酶1低，而肉芽肿巨噬细胞中一氧化氮合酶表达增加。有趣的是，一个离散的SSChighCD11b+I-A/I-EHighCD204+巨噬细胞亚群在LysMcreIl4ra−/lox中保留了甘露糖受体和YM1的表达，而在iLockcreIl4ra−/lox肉芽肿中不表达甘露糖受体。在Il4raφ/lox对照组小鼠中，AAM-−与寄生虫卵的距离很近，而在LysMcreIl4ra−/LOX小鼠中，Mmr+Ym1+巨噬细胞仅局限在肉芽肿周围，提示它们可能具有不同的功能。在体内，IL-10中和导致LysMcreIl4ra−/lox小鼠Mmr+Ym1+巨噬细胞消失。综上所述，这些结果表明，IL-4Rα反应性T细胞对于驱动替代巨噬细胞激活和控制肝脏肉芽肿性炎症是必不可少的。这些数据进一步表明，在缺乏巨噬细胞特异性IL-4Rα信号的情况下，IL-10能够驱动甘露糖受体和YM1阳性的巨噬细胞，与控制肝脏肉芽肿炎症有关。血吸虫病是一种由寄生虫血吸虫引起的热带疾病，全世界有超过2亿人感染血吸虫病。IL-4受体α(IL-4Rα)是IL-4和IL-13配体的共同受体链，通过IL-4受体α(IL-4R DNA)传递信号对于诱导保护性2型免疫反应和针对寄生虫卵的肉芽肿形成至关重要。在细胞特异性IL-4Rα缺陷小鼠的曼氏血吸虫感染和虫卵诱导的炎症研究中，研究了IL-4Rα激活的替代巨噬细胞(AAMφ)和IL-4Rα反应性T细胞在控制肝脏炎症和肉芽肿形成中的作用。有趣的是，AAMφ对肝肉芽肿的细胞组成或Th1型/Th2型细胞因子谱不是必需的。相反，依赖IL-4Rα的T细胞反应对于主要的Th2和IL-10反应以及肉芽肿中AAMφ的存在是重要的，从而避免肉芽肿细胞成分的重大破坏。此外，还鉴定了一个巨噬细胞亚群，这些细胞以IL-4Rφ不依赖于IL-4R但依赖于IL-10的方式表达甘露糖受体和YM1这两个AAMα标志物。这些细胞可能参与了炎症的控制。
IL-4Rα-dependent responses are essential for granuloma formation and host survival during acute schistosomiasis. Previously, we demonstrated that mice deficient for macrophage-specific IL-4Rα (LysMcreIl4ra−/lox) developed increased hepatotoxicity and gut inflammation; whereas inflammation was restricted to the liver of mice lacking T cell-specific IL-4Rα expression (iLckcreIl4ra−/lox). In the study presented here we further investigated their role in liver granulomatous inflammation. Frequencies and numbers of macrophage, lymphocyte or granulocyte populations, as well as Th1/Th2 cytokine responses were similar in Schistosoma mansoni-infected LysMcreIl4ra−/lox liver granulomas, when compared to Il4ra−/lox control mice. In contrast, a shift to Th1 responses with high IFN-γ and low IL-4, IL-10 and IL-13 was observed in the severely disrupted granulomas of iLckcreIl4ra−/lox and Il4ra−/− mice. As expected, alternative macrophage activation was reduced in both LysMcreIl4ra−/lox and iLckcreIl4ra−/lox granulomas with low arginase 1 and heightened nitric oxide synthase RNA expression in granuloma macrophages of both mouse strains. Interestingly, a discrete subpopulation of SSChighCD11b+I-A/I-EhighCD204+ macrophages retained expression of mannose receptor (MMR) and Ym1 in LysMcreIl4ra−/lox but not in iLckcreIl4ra−/lox granulomas. While aaMφ were in close proximity to the parasite eggs in Il4ra−/lox control mice, MMR+Ym1+ macrophages in LysMcreIl4ra−/lox mice were restricted to the periphery of the granuloma, indicating that they might have different functions. In vivo IL-10 neutralisation resulted in the disappearance of MMR+Ym1+ macrophages in LysMcreIl4ra−/lox mice. Together, these results show that IL-4Rα-responsive T cells are essential to drive alternative macrophage activation and to control granulomatous inflammation in the liver. The data further suggest that in the absence of macrophage-specific IL-4Rα signalling, IL-10 is able to drive mannose receptor- and Ym1-positive macrophages, associated with control of hepatic granulomatous inflammation. Schistosomiasis is a tropical disease caused by one of the species of the parasitic worm Schistosoma which infects over 200 million people worldwide. Signalling via the IL-4 receptor alpha (IL-4Rα), which is the common receptor chain for the ligands IL-4 and IL-13, is essential for inducing protective Type 2 immune response and granuloma formation in response to the parasite eggs. In experimental Schistosoma mansoni infection and egg-induced inflammation studies with cell type-specific IL-4Rα deficient mice, the role of IL-4Rα-activated alternative macrophages (aaMφ) and IL-4Rα-responsive T cells was investigated with focus on the control of hepatic inflammation and granuloma formation. Interestingly, aaMφ were not essential for the cellular composition or the Th1/Th2 cytokine profile in liver granulomas. In contrast, IL-4Rα-dependent T cell responses were important for predominant Th2 and IL-10 responses, as well as the presence of aaMφ in the granulomas, avoiding major disruption in the granuloma cell composition. Moreover, a macrophage subpopulation was identified and those cells expressed the two aaMφ markers, mannose receptor- and Ym1 in an IL-4Rα-independent but IL-10-dependent manner. These cells might be involved in the control of inflammation.
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影响因子：
7
作者：
GORDON, S;KESHAV, S;CHUNG, LP
通讯作者：
CHUNG, LP
影响因子：
3
作者：
Linehan, SA
通讯作者：
Linehan, SA
影响因子：
4.4
作者：
Atochina, O;Daly-Engel, T;Harn, DA
通讯作者：
Harn, DA
影响因子：
4.4
作者：
Fallon, PG;Richardson, EJ;McKenzie, ANJ
通讯作者：
McKenzie, ANJ
影响因子：
4.4
作者：
Hölscher, C;Arendse, B;Brombacher, F
通讯作者：
Brombacher, F