Therapeutic neutralization of the NLRP1 inflammasome reduces the innate immune response and improves histopathology after traumatic brain injury.
Therapeutic neutralization of the NLRP1 inflammasome reduces the innate immune response and improves histopathology after traumatic brain injury.
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DOI：
10.1038/jcbfm.2009.46
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发表时间：
2009-07
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创伤性脑损伤（TBI）诱发急性炎症，进而加重原发性脑损伤。免疫赦免中枢神经系统中先天免疫的关键部分涉及由炎性体信号传导介导的促炎细胞因子的产生。在这里，我们表明，核苷酸结合，富含亮氨酸的重复pyrin结构域包含蛋白1（NLRP 1）炎症体组成的NLRP 1，半胱天冬酶-1和-11，apoptosis相关的斑点样蛋白含有一个半胱天冬酶募集结构域（ASC），X-连锁抑制剂的凋亡蛋白（XIAP）和泛连接蛋白1在大脑皮层的神经元中表达。中度脊髓旁液压冲击伤（FPI）可诱导IL-1 β的加工、caspase-1的活化、XIAP的裂解和NLRP 1炎性体复合物的组装。在FPI后立即向损伤大鼠施用抗ASC中和抗体减少了半胱天冬酶-1活化、XIAP切割和IL-1β加工，导致挫伤体积显著减少。这些研究表明，NLRP 1炎性小体构成了TBI后先天性CNS炎症反应的重要组成部分，并可能成为减少创伤后脑炎症损伤作用的新治疗靶点。
Traumatic brain injury (TBI) elicits acute inflammation that in turn exacerbates primary brain damage. A crucial part of innate immunity in the immune privileged central nervous system involves production of proinflammatory cytokines mediated by inflammasome signaling. Here we show that the nucleotide-binding, leucine-rich repeat pyrin domain containing protein 1 (NLRP1) inflammasome consisting of NLRP1, caspases-1 and -11, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), the X-linked inhibitor of apoptosis protein (XIAP) and pannexin 1 is expressed in neurons of the cerebral cortex. Moderate parasagittal fluid percussion injury (FPI) induced processing of interleukin-1β (IL-1β), activation of caspase-1, cleavage of XIAP and promoted assembly of the NLRP1 inflammasome complex. Anti-ASC neutralizing antibodies administered immediately after FPI to injured rats reduced caspase-1 activation, XIAP cleavage and processing of IL-1β resulting in a significant decrease in contusion volume. These studies show that the NLRP1 inflammasome constitutes an important component of the innate CNS inflammatory response after TBI and may be a novel therapeutic target for reducing the damaging effects of post-traumatic brain inflammation.
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