Antibodies trap tissue migrating helminth larvae and prevent tissue damage by driving IL-4Rα-independent alternative differentiation of macrophages.
Antibodies trap tissue migrating helminth larvae and prevent tissue damage by driving IL-4Rα-independent alternative differentiation of macrophages.
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DOI：
10.1371/journal.ppat.1003771
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Harris NL
中科院分区：
文献类型：
--
作者：
Esser-von Bieren J;Mosconi I;Guiet R;Piersgilli A;Volpe B;Chen F;Gause WC;Seitz A;Verbeek JS;Harris NL
世界上大约三分之一的人口患有慢性蠕虫感染，目前还没有有效的疫苗可用。抗体和激活的巨噬细胞(AAM)构成对肠道蠕虫攻击感染的保护性免疫的关键组成部分。然而，抗体针对这些大型多细胞寄生虫的机制仍然不清楚。在蠕虫感染过程中巨噬细胞的交替激活与通过IL-4受体阿尔法链(IL-4Rα)的信号传递有关，但抗体对巨噬细胞分化的潜在影响尚未被探索。我们证明了蠕虫特异性抗体诱导组织迁移性蠕虫幼虫的快速捕获，并防止自然小鼠寄生虫多回螺旋体(HP)攻击感染后的组织坏死。缺乏抗体(JH−/−)或激活Fc受体(Fcrγ−/−)的小鼠体内有高度活动的幼虫，形成广泛的组织损伤，并在幼虫周围积累较少的表达精氨酸酶-1的巨噬细胞。此外，幽门螺杆菌特异性抗体在体外诱导依赖于γ和补体的巨噬细胞与幼虫的黏附，导致幼虫完全固定。抗体与蠕虫幼虫一起重新编程巨噬细胞，以表达伤口愈合相关基因，包括精氨酸酶-1，以及精氨酸酶-1的产物L-鸟氨酸直接损害幼虫的运动能力。抗体诱导的精氨酸酶-1在体外和体内的表达独立于IL-4Rα信号。综上所述，我们提出了一种新的依赖IL-4Rα的巨噬细胞交替激活机制，该机制依赖于抗体，既介导了抗蠕虫免疫，又防止了迁徙幼虫造成的组织破坏。在发展中国家，肠道蠕虫是一个紧迫的问题，约有20亿人患有慢性感染。到目前为止，还没有成功的疫苗可用，迫切需要从机制上详细了解抗蠕虫免疫，以改进预防和治疗战略。抗体是抵御肠道蠕虫攻击感染的保护性免疫的重要组成部分。然而，抗体针对这些大型多细胞寄生虫的确切机制仍然不清楚。我们现在证明蠕虫特异性抗体通过激活吞噬细胞来诱导组织迁移性蠕虫幼虫的快速捕获。在缺乏抗体或其受体的情况下，蠕虫感染的小鼠发生了广泛的组织损伤，揭示了抗体在限制寄生虫引起的组织破坏方面的新作用。此外，蠕虫特异性抗体对巨噬细胞重新编程，以表达伤口愈合因子，如精氨酸代谢酶精氨酸酶-1。有趣的是，精氨酸酶-1的产物L-鸟氨酸直接损害了蠕虫幼虫的运动能力。总之，我们的研究提供了关于抗体如何调节吞噬细胞功能以提供对大型多细胞寄生虫的保护的详细的机械性见解。我们的发现表明，新型抗蠕虫疫苗应该针对幼虫表面，并激活伤口愈合的巨噬细胞，以提供对组织破坏性幼虫的快速保护。
Approximately one-third of the world's population suffers from chronic helminth infections with no effective vaccines currently available. Antibodies and alternatively activated macrophages (AAM) form crucial components of protective immunity against challenge infections with intestinal helminths. However, the mechanisms by which antibodies target these large multi-cellular parasites remain obscure. Alternative activation of macrophages during helminth infection has been linked to signaling through the IL-4 receptor alpha chain (IL-4Rα), but the potential effects of antibodies on macrophage differentiation have not been explored. We demonstrate that helminth-specific antibodies induce the rapid trapping of tissue migrating helminth larvae and prevent tissue necrosis following challenge infection with the natural murine parasite Heligmosomoides polygyrus bakeri (Hp). Mice lacking antibodies (JH −/−) or activating Fc receptors (FcRγ−/−) harbored highly motile larvae, developed extensive tissue damage and accumulated less Arginase-1 expressing macrophages around the larvae. Moreover, Hp-specific antibodies induced FcRγ- and complement-dependent adherence of macrophages to larvae in vitro, resulting in complete larval immobilization. Antibodies together with helminth larvae reprogrammed macrophages to express wound-healing associated genes, including Arginase-1, and the Arginase-1 product L-ornithine directly impaired larval motility. Antibody-induced expression of Arginase-1 in vitro and in vivo occurred independently of IL-4Rα signaling. In summary, we present a novel IL-4Rα-independent mechanism of alternative macrophage activation that is antibody-dependent and which both mediates anti-helminth immunity and prevents tissue disruption caused by migrating larvae. Intestinal helminths present a pressing problem in developing countries with approximately 2 billion people suffering from chronic infection. To date no successful vaccines are available and a detailed mechanistic understanding of anti-helminth immunity is urgently needed to improve strategies for prevention and therapy. Antibodies form a crucial component of protective immunity against challenge infections with intestinal helminths. However, the exact mechanisms by which antibodies target these large multi-cellular parasites have remained obscure. We now demonstrate that helminth-specific antibodies induce the rapid trapping of tissue migrating helminth larvae by activating phagocytes. In the absence of antibodies or their receptors, helminth-infected mice developed extensive tissue damage, revealing a novel role for antibodies in limiting parasite-caused tissue disruption. Furthermore, helminth-specific antibodies reprogrammed macrophages to express wound-healing factors such as the arginine-metabolizing enzyme Arginase-1. Interestingly, the Arginase-1 product L-ornithine directly impaired the motility of helminth larvae. In summary, our study provides detailed mechanistic insights into how antibodies can modulate phagocyte function to provide protection against a large multi-cellular parasite. Our findings suggest that novel anti-helminth vaccines should target the larval surface and activate wound-healing macrophages to provide rapid protection against tissue-disruptive larvae.