NLRP1-dependent activation of Gasdermin D in neutrophils controls cutaneous leishmaniasis

IF 6.7 1区 医学 Q1 Immunology and Microbiology
Michiel Goris, Katiuska Passelli, Sanam Peyvandi, Miriam Díaz-Varela, Oaklyne Billion, Borja Prat-Luri, Benjamin Demarco, Chantal Desponds, Manon Termote, Eva Iniguez, Somaditya Dey, Bernard Malissen, Shaden Kamhawi, Benjamin P. Hurrell, Petr Broz, Fabienne Tacchini-Cottier
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Abstract

Intracellular pathogens that replicate in host myeloid cells have devised ways to inhibit the cell’s killing machinery. Pyroptosis is one of the host strategies used to reduce the pathogen replicating niche and thereby control its expansion. The intracellular Leishmania parasites can survive and use neutrophils as a silent entry niche, favoring subsequent parasite dissemination into the host. Here, we show that Leishmania mexicana induces NLRP1- and caspase-1-dependent Gasdermin D (GSDMD)-mediated pyroptosis in neutrophils, a process critical to control the parasite-induced pathology. In the absence of GSDMD, we observe an increased number of infected dermal neutrophils two days post-infection. Using adoptive neutrophil transfer in neutropenic mice, we show that pyroptosis contributes to the regulation of the neutrophil niche early after infection. The critical role of neutrophil pyroptosis and its positive influence on the regulation of the disease outcome was further demonstrated following infection of mice with neutrophil-specific deletion of GSDMD. Thus, our study establishes neutrophil pyroptosis as a critical regulator of leishmaniasis pathology.
中性粒细胞中依赖 NLRP1 激活的 Gasdermin D 可控制皮肤利什曼病
在宿主骨髓细胞中复制的细胞内病原体已经设计出了抑制细胞杀伤机制的方法。嗜热细胞增多症是宿主用来减少病原体复制生态位从而控制其扩张的策略之一。细胞内的利什曼原虫可以存活下来,并利用中性粒细胞作为无声的进入龛位,有利于寄生虫随后传播到宿主体内。在这里,我们发现墨西哥利什曼原虫会诱导中性粒细胞发生依赖 NLRP1 和 Caspase-1 的 Gasdermin D(GSDMD)介导的热凋亡,这一过程对于控制寄生虫诱导的病理变化至关重要。在 GSDMD 缺失的情况下,我们观察到感染后两天受感染的真皮中性粒细胞数量增加。通过在中性粒细胞嗜中性小鼠中进行收养性中性粒细胞转移,我们发现嗜中性粒细胞热解有助于在感染后早期调节中性粒细胞生态位。在中性粒细胞特异性缺失 GSDMD 的小鼠感染后,我们进一步证实了中性粒细胞热解的关键作用及其对疾病结局调节的积极影响。因此,我们的研究确定了中性粒细胞的嗜热性是利什曼病病理学的一个关键调节因子。
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来源期刊
PLoS Pathogens
PLoS Pathogens 生物-病毒学
CiteScore
11.40
自引率
3.00%
发文量
598
审稿时长
2 months
期刊介绍: Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.
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