Efferocytosis drives myeloid NLRP3 dependent inflammasome signaling secretion of IL-1β to promote tumor growth.
Efferocytosis drives myeloid NLRP3 dependent inflammasome signaling secretion of IL-1β to promote tumor growth.
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Effercell作用驱动髓系NLRP3依赖的炎症体信号IL-1β的分泌，促进肿瘤生长。
DOI：
10.3389/fimmu.2022.993771
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发表时间：
2022
影响因子：
7.3
通讯作者：
Kim, Young J.
中科院分区：
文献类型：
--
作者：
Lang, Cara;Roy, Sohini;Wang, Yu;Graves, Diana;Xu, Yaomin;Serezani, C. Henrique;Korrer, Michael;Kim, Young J.
髓系抑制细胞中的Caspase-1信号可以促进t细胞不依赖的癌症进展，但在肿瘤环境中高度异质性的髓系群体中，炎性体信号的调节仍然是难以捉摸的。为了解决这一复杂性，头颈部鳞状细胞癌（HNSCC）的单细胞转录组学分析在肿瘤浸润性骨髓细胞的特定簇中发现了不同的炎性体相关基因。在这些髓系细胞中，传感器蛋白、NLRP3和下游效应因子IL-1β转录物在TME中分散的单核细胞和巨噬细胞亚型中富集。我们发现NLRP3的缺失，而不是AIM2的缺失，在体内表型上影响了caspase-1/IL-1β依赖性肿瘤的进展。矛盾的是，我们发现骨髓内固有的caspase-1信号增加了骨髓存活，这与caspase-1典型的焦亡功能所预测的相反。发现髓系NLRP3/IL-1β信号轴促进肿瘤生长是不依赖于气皮蛋白D的。在机制上，我们发现TME中吞噬细胞介导的垂死肿瘤细胞的efferocytosis直接激活nlrp3依赖的炎性小体信号，从而驱动IL-1β的分泌。随后，我们发现nlrp3介导的IL-1β的产生在体内驱动肿瘤生长。动态RNA速度分析显示，从efferocytosis基因集高的巨噬细胞到炎性体基因集高的巨噬细胞群体有一个强大的定向流动。我们提供了一种新的efferocysyis依赖性炎性小体信号通路，介导稳态肿瘤细胞凋亡，这是慢性炎症诱导的恶性肿瘤的特征。
Caspase-1 signaling in myeloid suppressor cells can promote T-cell independent cancer progression, but the regulation of inflammasome signaling within the highly heterogeneous myeloid population in the tumor milieu remains elusive. To resolve this complexity, single cell transcriptomic profile of Head and Neck Squamous Cell Carcinoma (HNSCC) identified distinct inflammasome-associated genes within specific clusters of tumor-infiltrating myeloid cells. Among these myeloid cells, the sensor protein, NLRP3, and downstream effector IL-1β transcripts were enriched in discreet monocytic and macrophage subtypes in the TME. We showed that deletion of NLRP3, but not AIM2, phenocopied caspase-1/IL-1β dependent tumor progression in vivo. Paradoxically, we found myeloid-intrinsic caspase-1 signaling increased myeloid survival contrary to what would be predicted from the canonical pyroptotic function of caspase-1. This myeloid NLRP3/IL-1β signaling axis promotion of tumor growth was found to be gasdermin D independent. Mechanistically, we found that phagocyte-mediated efferocytosis of dying tumor cells in the TME directly activated NLRP3-dependent inflammasome signaling to drive IL-1β secretion. Subsequently we showed that NLRP3-mediated IL-1β production drives tumor growth in vivo. Dynamic RNA velocity analysis showed a robust directional flow from efferocytosis gene-set high macrophages to an inflammasome gene-set high macrophage population. We provide a novel efferocytosis-dependent inflammasome signaling pathway which mediates homeostatic tumor cell apoptosis that characterizes chronic inflammation-induced malignancy.
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影响因子：
9
作者：
Fucikova J;Kepp O;Kasikova L;Petroni G;Yamazaki T;Liu P;Zhao L;Spisek R;Kroemer G;Galluzzi L
通讯作者：
Galluzzi L
DOI：
10.1084/jem.20161707
发表时间：
2017-06-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Daley D;Mani VR;Mohan N;Akkad N;Pandian GSDB;Savadkar S;Lee KB;Torres-Hernandez A;Aykut B;Diskin B;Wang W;Farooq MS;Mahmud AI;Werba G;Morales EJ;Lall S;Wadowski BJ;Rubin AG;Berman ME;Narayanan R;Hundeyin M;Miller G
通讯作者：
Miller G
影响因子：
46.9
作者：
Cortal, Akira;Martignetti, Loredana;Rausell, Antonio
通讯作者：
Rausell, Antonio
DOI：
10.4049/jimmunol.1601520
发表时间：
2017-02-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Elliott MR;Koster KM;Murphy PS
通讯作者：
Murphy PS
DOI：
10.1083/jcb.201004096
发表时间：
2010-06-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Elliott MR;Ravichandran KS
通讯作者：
Ravichandran KS