The Nlrp3 inflammasome, IL-1β, and neutrophil recruitment are required for susceptibility to a nonhealing strain of Leishmania major in C57BL/6 mice
The Nlrp3 inflammasome, IL-1β, and neutrophil recruitment are required for susceptibility to a nonhealing strain of Leishmania major in C57BL/6 mice
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DOI：
10.1002/eji.201546015
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发表时间：
2016-04-01
影响因子：
5.4
通讯作者：
Sacks, David L.
中科院分区：
文献类型：
--
作者：
Charmoy, Melanie;Hurrell, Benjamin P.;Sacks, David L.
用大多数主要利什曼原虫株感染C57BL/6小鼠，可导致皮肤损伤愈合和寄生虫清除。从慢性皮损患者分离的主要塞德曼菌株(LMSD)感染C57BL/6小鼠，尽管引发了强烈的Th1反应，但导致病变无法愈合，寄生虫清除不良，耳部真皮完全破坏。我们在这里表明，与愈合菌株相比，LMSD可引起IL-1βmRNA和产生IL-1β的真皮细胞的早期上调，并显著地将中性粒细胞募集到受感染的皮肤。缺乏Nlrp3的小鼠，或缺乏IL-1β或IL-1受体信号的Nlrp3，或缺乏IL-1β或IL-1受体信号的凋亡相关斑点样蛋白(含有caspase-1/11)，会出现愈合损伤并清除感染部位的lmsd。对lmsd耐药的小鼠有更强的抗原特异性Th1反应。在中性粒细胞减少的Genista小鼠身上观察到的愈合情况支持了IL-1β可能通过中性粒细胞募集来局部抑制免疫的可能性。LMSD感染的巨噬细胞体外分泌成熟的IL-1β依赖于Nlrp3炎症体和caspase-1的激活。这些数据表明，Nlrp3炎症体依赖的IL-1β与局部的中性粒细胞募集有关，在常规耐药小鼠皮肤利什曼病的发展中起着关键作用。
Infection of C57BL/6 mice with most Leishmania major strains results in a healing lesion and clearance of parasites from the skin. Infection of C57BL/6 mice with the L. major Seidman strain (LmSd), isolated from a patient with chronic lesions, despite eliciting a strong Th1 response, results in a nonhealing lesion, poor parasite clearance, and complete destruction of the ear dermis. We show here that in comparison to a healing strain, LmSd elicited early upregulation of IL-1 beta mRNA and IL-1 beta-producing dermal cells and prominent neutrophil recruitment to the infected skin. Mice deficient in Nlrp3, apoptosis-associated speck-like protein containing a caspase recruitment domain, or caspase-1/11, or lacking IL-1 beta or IL-1 receptor signaling, developed healing lesions and cleared LmSd from the infection site. Mice resistant to LmSd had a stronger antigen-specific Th1 response. The possibility that IL-1 beta might act through neutrophil recruitment to locally suppress immunity was supported by the healing observed in neutropenic Genista mice. Secretion of mature IL-1 beta by LmSd-infected macrophages in vitro was dependent on activation of the Nlrp3 inflammasome and caspase-1. These data reveal that Nlrp3 inflammasome-dependent IL-1 beta, associated with localized neutrophil recruitment, plays a crucial role in the development of a nonhealing form of cutaneous leishmaniasis in conventionally resistant mice.