Sertoli cells have a functional NALP3 inflammasome that can modulate autophagy and cytokine production.
Sertoli cells have a functional NALP3 inflammasome that can modulate autophagy and cytokine production.
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DOI：
10.1038/srep18896
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发表时间：
2016-01-08
影响因子：
4.6
通讯作者：
Fernández N
中科院分区：
文献类型：
--
作者：
Hayrabedyan S;Todorova K;Jabeen A;Metodieva G;Toshkov S;Metodiev MV;Mincheff M;Fernández N
支持细胞可作为非专职的致耐受性抗原提呈细胞，并维持由其紧密连接形成的血-睾丸屏障。NOD样受体家族成员和NALP 3炎性体在促炎性先天免疫信号通路中起关键作用。关于NOD 1和NOD 2在人和小鼠支持细胞中的表达的数据有限。目前，还没有关于支持细胞中炎性小体表达或功能的数据。我们发现，在原代青春期前的Sertoli细胞和成人Sertoli细胞系中，TLR 4\NOD 1和NOD 2的相互作用在NFκB活化中会聚，并引发NALP 3活化，导致从头合成和炎性体引发。这导致半胱天冬酶-1活化和IL-1β分泌。我们证明了这个过程是由与自噬相关的机制控制的。NOD 1促进pro-IL-1β限制和自噬体成熟停滞，而NOD 2促进caspase-1激活、IL-1β分泌和自噬成熟。NALP 3调节NOD 1和pro-IL-1β表达，而NOD 2反向促进IL-1β表达。本研究证明了支持细胞在特异性刺激下通过炎症细胞因子诱导参与男性不育的发病机制。
Sertoli cells, can function as non-professional tolerogenic antigen-presenting cells, and sustain the blood-testis barrier formed by their tight junctions. The NOD-like receptor family members and the NALP3 inflammasome play a key role in pro-inflammatory innate immunity signalling pathways. Limited data exist on NOD1 and NOD2 expression in human and mouse Sertoli cells. Currently, there is no data on inflammasome expression or function in Sertoli cells. We found that in primary pre-pubertal Sertoli cells and in adult Sertoli line, TLR4\NOD1 and NOD2 crosstalk converged in NFκB activation and elicited a NALP3 activation, leading to de novo synthesis and inflammasome priming. This led to caspase-1 activation and IL-1β secretion. We demonstrated this process was controlled by mechanisms linked to autophagy. NOD1 promoted pro-IL-1β restriction and autophagosome maturation arrest, while NOD2 promoted caspase-1 activation, IL-1β secretion and autophagy maturation. NALP3 modulated NOD1 and pro-IL-1β expression, while NOD2 inversely promoted IL-1β. This study is proof of concept that Sertoli cells, upon specific stimulation, could participate in male infertility pathogenesis via inflammatory cytokine induction.