A Role for Granzyme M in TLR4-Driven Inflammation and Endotoxicosis
A Role for Granzyme M in TLR4-Driven Inflammation and Endotoxicosis
复制标题
DOI：
10.4049/jimmunol.1000430
复制
发表时间：
2010-08-01
影响因子：
4.4
通讯作者：
Smyth, Mark J.
中科院分区：
文献类型：
--
作者：
Anthony, Desiree A.;Andrews, Daniel M.;Smyth, Mark J.
淋巴细胞穿孔素和丝氨酸蛋白酶颗粒酶是公认的细胞凋亡的外源性介质。我们现在证明，细胞毒性淋巴细胞颗粒成分在TLR4结扎反应中深刻地增强了髓细胞炎症细胞因子级联反应。caspase-1缺陷小鼠对LPS完全耐药，而穿孔素缺陷小鼠血清细胞因子产生减少，对致死性内毒素中毒产生抗性，这表明颗粒酶的作用。一致地，颗粒酶M （GrzM）的缺乏导致血清IL-1 α、IL-1 β、TNF和ifn - γ水平降低，并显著降低致死性内毒素中毒的易感性。在颗粒酶a缺乏而不是颗粒酶b缺乏的小鼠中也观察到这些改变的反应。研究强调了APC-NK细胞串扰在炎症级联中的作用，因为GrzM仅由NK细胞表达，并且在rag1 /GrzM双缺陷背景下也观察到对LPS的抗性。总的来说，这些数据表明NK细胞GrzM增加了LPS-TLR4信号下游的炎症级联，最终导致致命的内毒素中毒。最重要的是，这些数据表明颗粒酶不应再仅仅被认为是细胞凋亡的介质，而是作为炎症的潜在关键调节剂。免疫学杂志，2010,18(5):1794-1803。
Lymphocyte perforin and serine protease granzymes are well-recognized extrinsic mediators of apoptosis. We now demonstrate that cytotoxic lymphocyte granule components profoundly augment the myeloid cell inflammatory cytokine cascade in response to TLR4 ligation. Whereas caspase-1-deficient mice were completely resistant to LPS, reduced serum cytokine production and resistance to lethal endotoxicosis were also obtained with perforin-deficient mice, indicating a role for granzymes. Consistently, a lack of granzyme M (GrzM) resulted in reduced serum IL-1 alpha, IL-1 beta, TNF, and IFN-gamma levels and significantly reduced susceptibility to lethal endotoxicosis. These altered responses were also observed in granzyme A-deficient but not granzyme B-deficient mice. A role for APC-NK cell cross-talk in the inflammatory cascade was highlighted, as GrzM was exclusively expressed by NK cells and resistance to LPS was also observed on a RAG-1/GrzM-double deficient background. Collectively, the data suggest that NK cell GrzM augments the inflammatory cascade downstream of LPS-TLR4 signaling, which ultimately results in lethal endotoxicosis. Most importantly, these data demonstrate that granzymes should no longer be considered solely as mediators of apoptosis, but additionally as potential key regulators of inflammation. The Journal of Immunology, 2010, 185: 1794-1803.