Phagolysosome acidification is required for silica and engineered nanoparticle-induced lysosome membrane permeabilization and resultant NLRP3 inflammasome activity.
Phagolysosome acidification is required for silica and engineered nanoparticle-induced lysosome membrane permeabilization and resultant NLRP3 inflammasome activity.
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DOI：
10.1016/j.taap.2017.01.012
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发表时间：
2017-03-01
影响因子：
3.8
通讯作者：
Holian A
中科院分区：
文献类型：
--
作者：
Jessop F;Hamilton RF Jr;Rhoderick JF;Fletcher P;Holian A
NLRP 3炎性小体激活响应于有害颗粒暴露而发生，并且对于颗粒诱导的肺部疾病的发展至关重要。溶酶体膜透化（LMP）的机制（吸入颗粒激活NLRP 3炎性体的中心途径）尚未完全理解。我们证明，溶酶体vATP酶抑制剂巴弗洛霉素A1阻断LMP在体外和离体暴露于二氧化硅，多壁碳纳米管，钛纳米带后，在原代小鼠巨噬细胞。巴弗洛霉素A1处理颗粒暴露的巨噬细胞也导致细胞溶质中活性组织蛋白酶L降低，这是泄漏的组织蛋白酶B的替代指标，与NLRP 3炎性小体活性降低相关。二氧化硅诱导的LMP部分依赖于溶酶体组织蛋白酶B和L，而纳米颗粒诱导的LMP发生独立的组织蛋白酶活性。此外，用CA-074-Me抑制溶酶体组织蛋白酶活性降低了高迁移率族蛋白盒1的释放。总之，这些数据支持这样的观点，即溶酶体酸化是颗粒诱导的LMP的先决条件，并且由此产生的溶酶体组织蛋白酶的泄漏是进行中的NLRP 3炎性体活性和HMGB 1释放的主要调节剂。
NLRP3 inflammasome activation occurs in response to hazardous particle exposures and is critical for the development of particle-induced lung disease. Mechanisms of Lysosome Membrane Permeabilization (LMP), a central pathway for activation of the NLRP3 inflammasome by inhaled particles, are not fully understood. We demonstrate that the lysosomal vATPases inhibitor Bafilomycin A1 blocked LMP in vitro and ex vivo in primary murine macrophages following exposure to silica, multi-walled carbon nanotubes, and titanium nanobelts. Bafilomycin A1 treatment of particle-exposed macrophages also resulted in decreased active cathepsin L in the cytosol, a surrogate measure for leaked cathepsin B, which was associated with less NLRP3 inflammasome activity. Silica-induced LMP was partially dependent upon lysosomal cathepsins B and L, whereas nanoparticle-induced LMP occurred independent of cathepsin activity. Furthermore, inhibition of lysosomal cathepsin activity with CA-074-Me decreased the release of High Mobility Group Box 1. Together, these data support the notion that lysosome acidification is a prerequisite for particle-induced LMP, and the resultant leak of lysosome cathepsins is a primary regulator of ongoing NLRP3 inflammasome activity and release of HMGB1.