L-plastin enhances NLRP3 inflammasome assembly and bleomycin-induced lung fibrosis.
L-plastin enhances NLRP3 inflammasome assembly and bleomycin-induced lung fibrosis.
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L-普拉斯汀增强了NLRP3炎性体组装和博来霉素诱导的肺纤维化。
DOI：
10.1016/j.celrep.2022.110507
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发表时间：
2022-03-15
期刊：
影响因子：
8.8
通讯作者：
Morley SC
中科院分区：
文献类型：
--
作者：
Joshi H;Almgren-Bell A;Anaya EP;Todd EM;Van Dyken SJ;Seth A;McIntire KM;Singamaneni S;Sutterwala F;Morley SC
巨噬细胞粘附和拉伸可诱导白细胞介素(IL)-1β的产生，但这种机械转导的机制尚不清楚。在这里，我们明确了组织内巨噬细胞的机械张力和控制IL-1β产生的NLRP3炎性体的激活之间的分子联系。NLRP3的激活增强了抗菌防御，但过度的NLRP3活性会导致肺纤维化和急性呼吸窘迫综合征等炎症组织损伤。我们发现肌动蛋白捆绑蛋白L-plastin （LPL）显著增强NLRP3的组装。具体来说，LPL通过稳定ASC与激酶Pyk2的相互作用，使NLRP3组装过程中含有caspase激活和募集结构域（ASC）的凋亡相关斑点样蛋白寡聚化，激酶Pyk2是细胞表面粘附结构podosomes的组成部分。在外源性NLRP3激活剂治疗后，缺乏LPL的肺内肺泡巨噬细胞（AMs）表现出caspase-1活性、IL-1β裂解和气皮素- d加工降低。LPL - / -小鼠对博莱霉素诱导的肺损伤和纤维化表现出抗性。这些发现确定了LPL-Pyk2-ASC通路是nlrp3介导的炎症条件调节的靶标。在这项研究中，Joshi等人发现了肺炎症的关键调节剂l -活蛋白。L-plastin支持巨噬细胞炎症反应，在肺损伤期间通过连接炎症和机械刺激来增强肺纤维化，这一过程称为机械转导。本研究结果将有助于确定诊断和治疗肺部炎症性疾病的有效靶点。
Macrophage adhesion and stretching have been shown to induce interleukin (IL)-1β production, but the mechanism of this mechanotransduction remains unclear. Here we specify the molecular link between mechanical tension on tissue-resident macrophages and activation of the NLRP3 inflammasome, which governs IL-1β production. NLRP3 activation enhances antimicrobial defense, but excessive NLRP3 activity causes inflammatory tissue damage in conditions such as pulmonary fibrosis and acute respiratory distress syndrome. We find that the actin-bundling protein L-plastin (LPL) significantly enhances NLRP3 assembly. Specifically, LPL enables apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) oligomerization during NLRP3 assembly by stabilizing ASC interactions with the kinase Pyk2, a component of cell-surface adhesive structures called podosomes. Upon treatment with exogenous NLRP3 activators, lung-resident alveolar macrophages (AMs) lacking LPL exhibit reduced caspase-1 activity, IL-1β cleavage, and gasdermin-D processing. LPL−/− mice display resistance to bleomycin-induced lung injury and fibrosis. These findings identify the LPL-Pyk2-ASC pathway as a target for modulation in NLRP3-mediated inflammatory conditions. In this study, Joshi et al. identify a crucial modulator, L-plastin, in lung inflammation. L-plastin supports the macrophage inflammatory response to enhance lung fibrosis during lung injury by connecting inflammation and mechanical stimuli in a process called mechanotransduction. The findings from this study will help determine efficient targets for diagnosis and treatment of lung inflammatory diseases.
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影响因子：
7.2
作者：
de Zoete, Marcel R.;Palm, Noah W.;Flavell, Richard A.
通讯作者：
Flavell, Richard A.
影响因子：
32.4
作者：
Chen, H;Mocsai, A;Brown, EJ
通讯作者：
Brown, EJ
影响因子：
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作者：
Carpentier, Samuel J.;Ni, Minjian;Hamerman, Jessica A.
通讯作者：
Hamerman, Jessica A.
DOI：
10.1152/ajplung.00393.2017
发表时间：
2018-03-01
影响因子：
4.9
作者：
Cho, Soo Jung;Rooney, Kristen;Stout-Delgado, Heather W.
通讯作者：
Stout-Delgado, Heather W.
DOI：
10.1164/rccm.200808-1274oc
发表时间：
2009-05-15
影响因子：
24.7
作者：
Gasse, Pamela;Riteau, Nicolas;Couillin, Isabelle
通讯作者：
Couillin, Isabelle