Granzyme A in Human Platelets Regulates the Synthesis of Proinflammatory Cytokines by Monocytes in Aging.
Granzyme A in Human Platelets Regulates the Synthesis of Proinflammatory Cytokines by Monocytes in Aging.
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DOI：
10.4049/jimmunol.1700885
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发表时间：
2018-01-01
期刊：
影响因子：
--
通讯作者：
Rondina MT
中科院分区：
文献类型：
--
作者：
Campbell RA;Franks Z;Bhatnagar A;Rowley JW;Manne BK;Supiano MA;Schwertz H;Weyrich AS;Rondina MT
炎症失调与衰老的病理生物学有关，但对衰老过程中血小板-白细胞相互作用和下游细胞因子合成的了解仍然很少。从健康的年轻（年龄<45，n=37）和老年（年龄≥65，n=30）成人中分离血小板和单核细胞，并在自体和非自体条件下一起孵育。检查了单核细胞单独或在血小板存在下的炎性细胞因子的合成。下一代RNA测序允许无偏地分析衰老中的血小板转录组。基础IL-8和MCP-1的合成单核细胞单独没有老年人和年轻人之间的差异。然而，在自体血小板存在下，来自老年人的单核细胞比年轻人合成更多的IL-8（41±5对9±2 ng/mL，p<0.0001）和MCP-1（867±150对216±36 ng/mL，p<0.0001）。来自老年人的血小板足以上调单核细胞的炎性细胞因子的合成。使用血小板的RNA-seq，然后通过RT-PCR和免疫印迹进行验证，我们发现颗粒酶A（GrmA），一种先前未在人类血小板中鉴定的丝氨酸蛋白酶，在衰老中增加（与年轻成人相比约9倍，p<0.05），并通过TLR 4和半胱天冬酶-1控制IL-8和MCP-1合成的增加。抑制GrmA可将衰老过程中过量的IL-8和MCP-1合成降低至与年轻成人相似的水平。总之，人类衰老与血小板转录组和蛋白质组的变化有关。GrmA存在于人血小板中并具有生物活性，在老年人中更高，并控制单核细胞合成炎性细胞因子。血小板分子特征和单核细胞信号的改变可能导致老年人炎症综合征失调。
Dysregulated inflammation is implicated in the pathobiology of aging, yet platelet-leukocyte interactions and downstream cytokine synthesis in aging remains poorly understood. Platelets and monocytes were isolated from healthy younger (age<45, n=37) and older (age≥65, n=30) adults and incubated together under autologous and non-autologous conditions. Synthesis of inflammatory cytokines by monocytes, alone or in the presence of platelets, was examined. Next-generation RNA-sequencing allowed for unbiased profiling of the platelet transcriptome in aging. Basal IL-8 and MCP-1 synthesis by monocytes alone did not differ between older and younger adults. However, in the presence of autologous platelets, monocytes from older adults synthesized greater IL-8 (41±5 vs. 9±2 ng/mL, p<0.0001) and MCP-1 (867±150 vs. 216±36 ng/mL, p<0.0001) than younger adults. Platelets from older adults were sufficient for upregulating the synthesis of inflammatory cytokines by monocytes. Using RNA-seq of platelets followed by validation via RT-PCR and immunoblot, we discovered that granzyme A (GrmA), a serine protease not previously identified in human platelets, is increased in aging (~9-fold vs. younger adults, p<0.05) and governs increased IL-8 and MCP-1 synthesis through TLR4 and caspase-1. Inhibiting GrmA reduced excessive IL-8 and MCP-1 synthesis in aging to levels similar to younger adults. In summary, human aging is associated with changes in the platelet transcriptome and proteome. GrmA is present and bioactive in human platelets, is higher in older adults, and controls the synthesis of inflammatory cytokines by monocytes. Alterations in the platelet molecular signature and signaling to monocytes may contribute to dysregulated inflammatory syndromes in older adults.
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血小板中的炎性体：传染性和无菌疾病的盟友凝结和炎症？
影响因子：
4.6
作者：
Hottz ED;Monteiro AP;Bozza FA;Bozza PT
通讯作者：
Bozza PT
影响因子：
6.3
作者：
Mohebali D;Kaplan D;Carlisle M;Supiano MA;Rondina MT
通讯作者：
Rondina MT
影响因子：
4.4
作者：
Anthony, Desiree A.;Andrews, Daniel M.;Smyth, Mark J.
通讯作者：
Smyth, Mark J.
影响因子：
7.5
作者：
Rondina, Matthew T.;Grissom, Colin K.;Weyrich, Andrew S.
通讯作者：
Weyrich, Andrew S.
DOI：
10.1111/j.1538-7836.2011.04208.x
发表时间：
2011-04
期刊：
Journal of thrombosis and haemostasis : JTH
影响因子：
--
作者：
Rondina MT;Schwertz H;Harris ES;Kraemer BF;Campbell RA;Mackman N;Grissom CK;Weyrich AS;Zimmerman GA
通讯作者：
Zimmerman GA