Caspase-8 inhibition improves the outcome of bacterial infections in mice by promoting neutrophil activation.
Caspase-8 inhibition improves the outcome of bacterial infections in mice by promoting neutrophil activation.
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DOI：
10.1016/j.xcrm.2023.101098
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发表时间：
2023-07-18
影响因子：
14.3
通讯作者：
Teti, Giuseppe
中科院分区：
文献类型：
--
作者：
Lentini, Germana;Fama, Agata;De Gaetano, Giuseppe Valerio;Coppolino, Francesco;Mahjoub, Ahlem Khachroub;Ryan, Liv;Lien, Egil;Espevik, Terje;Beninati, Concetta;Teti, Giuseppe
在分化过程中，中性粒细胞经历了自发的促炎程序，这里假设是在caspase-8的控制下。在小鼠中，腹腔注射caspase-8抑制剂z-IETD-fmk足以在没有细胞死亡的情况下释放促炎细胞因子和中性粒细胞内流的产生。这些作用是由于选择性抑制caspase-8，并且需要强补性干扰素-β (IFN-β)的产生和RIPK3，但不需要MLKL，后者是坏死细胞死亡的重要下游刽子手。在体外，z-IETD-fmk刺激足以在小鼠中性粒细胞中诱导显著的细胞因子产生，但在巨噬细胞中却没有。治疗性用药z-IETD-fmk通过增加细胞因子释放、中性粒细胞内流和细菌清除，改善致死性细菌性腹膜炎和肺炎模型的临床结果。此外，该抑制剂还能保护小鼠免受大剂量内毒素休克。总的来说，我们的数据揭示了一个RIPK3-和IFN-β依赖的途径，该途径在中性粒细胞中组成性激活，可以利用caspase-8抑制进行治疗。Caspase-8控制中性粒细胞组成性激活的炎症途径，该途径依赖于补补性IFN-β的产生和RIPK3，但不依赖于MLKL。Caspase-8抑制诱导趋化因子的产生和中性粒细胞的募集。Caspase-8抑制对致死性细菌感染有治疗作用。Caspase-8在体内平衡过程中防止炎症，但其潜在机制尚不清楚。Lentini等人的研究表明，caspase-8在中性粒细胞中负调控由RIPK3激酶驱动并由干扰素-β维持的自发促炎途径。通过释放这一途径，药物抑制caspase-8诱导中性粒细胞动员，可以有效治疗细菌感染。
During differentiation, neutrophils undergo a spontaneous pro-inflammatory program that is hypothesized here to be under caspase-8 control. In mice, intraperitoneal administration of the caspase-8 inhibitor z-IETD-fmk is sufficient to unleash the production of pro-inflammatory cytokines and neutrophil influx in the absence of cell death. These effects are due to selective inhibition of caspase-8 and require tonic interferon-β (IFN-β) production and RIPK3 but not MLKL, the essential downstream executioner of necroptotic cell death. In vitro, stimulation with z-IETD-fmk is sufficient to induce significant cytokine production in murine neutrophils but not in macrophages. Therapeutic administration of z-IETD-fmk improves clinical outcome in models of lethal bacterial peritonitis and pneumonia by augmenting cytokine release, neutrophil influx, and bacterial clearance. Moreover, the inhibitor protects mice against high-dose endotoxin shock. Collectively, our data unveil a RIPK3- and IFN-β-dependent pathway that is constitutively activated in neutrophils and can be harnessed therapeutically using caspase-8 inhibition. Caspase-8 controls a constitutively activated inflammatory pathway in neutrophils This pathway is dependent on tonic IFN-β production and RIPK3 but not MLKL Caspase-8 inhibition induces chemokine production and neutrophil recruitment Caspase-8 inhibition has therapeutic effects against lethal bacterial infection Caspase-8 prevents inflammation during homeostasis, but the underlying mechanisms are unclear. Lentini et al. show that caspase-8 negatively regulates—in neutrophils—a spontaneous pro-inflammatory pathway driven by the RIPK3 kinase and sustained by interferon-β. By unleashing this pathway, pharmacological caspase-8 inhibition induces neutrophil mobilization and can effectively treat bacterial infections.
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影响因子：
168.9
作者：
Holmes, Alison H.;Moore, Luke S. P.;Piddock, Laura J. V.
通讯作者：
Piddock, Laura J. V.
caspase-8可调节dectin-1和补体受体3驱动的IL-1β产生，以响应于β-葡聚糖和真菌病原体念珠菌白色念珠菌。
DOI：
10.4049/jimmunol.1400276
发表时间：
2014-09-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Ganesan S;Rathinam VAK;Bossaller L;Army K;Kaiser WJ;Mocarski ES;Dillon CP;Green DR;Mayadas TN;Levitz SM;Hise AG;Silverman N;Fitzgerald KA
通讯作者：
Fitzgerald KA
影响因子：
7.3
作者：
Landwehr-Kenzel S;Henneke P
通讯作者：
Henneke P
影响因子：
4.4
作者：
Lentini, Germana;Fama, Agata;Midiri, Angelina
通讯作者：
Midiri, Angelina
影响因子：
32.4
作者：
Kang, Tae-Bong;Yang, Seung-Hoon;Wallach, David
通讯作者：
Wallach, David