Dataset Information

A subpopulation of CD146⁺ macrophages enhances antitumor immunity by activating the NLRP3 inflammasome.

ABSTRACT: As one of the main tumor-infiltrating immune cell types, tumor-associated macrophages (TAMs) determine the efficacy of immunotherapy. However, limited knowledge about their phenotypically and functionally heterogeneous nature restricts their application in tumor immunotherapy. In this study, we identified a subpopulation of CD146⁺ TAMs that exerted antitumor activity in both human samples and animal models. CD146 expression in TAMs was negatively controlled by STAT3 signaling. Reducing this population of TAMs promoted tumor development by facilitating myeloid-derived suppressor cell recruitment via activation of JNK signaling. Interestingly, CD146 was involved in the NLRP3 inflammasome-mediated activation of macrophages in the tumor microenvironment, partially by inhibiting transmembrane protein 176B (TMEM176B), an immunoregulatory cation channel. Treatment with a TMEM176B inhibitor enhanced the antitumor activity of CD146⁺ TAMs. These data reveal a crucial antitumor role of CD146⁺ TAMs and highlight the promising immunotherapeutic approach of inhibiting CD146 and TMEM176B.

SUBMITTER: Jing L

PROVIDER: S-EPMC10387481 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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A subpopulation of CD146<sup>+</sup> macrophages enhances antitumor immunity by activating the NLRP3 inflammasome.

Jing Lin L An Yunhe Y Cai Tanxi T Xiang Jianquan J Li Baoming B Guo Jiang J Ma Xinran X Wei Ling L Tian Yanjie Y Cheng Xiaoyan X Chen Xuehui X Liu Zheng Z Feng Jing J Yang Fuquan F Yan Xiyun X Duan Hongxia H

Cellular & molecular immunology 20230612 8

As one of the main tumor-infiltrating immune cell types, tumor-associated macrophages (TAMs) determine the efficacy of immunotherapy. However, limited knowledge about their phenotypically and functionally heterogeneous nature restricts their application in tumor immunotherapy. In this study, we identified a subpopulation of CD146<sup>+</sup> TAMs that exerted antitumor activity in both human samples and animal models. CD146 expression in TAMs was negatively controlled by STAT3 signaling. Reducin ...[more]

PMID: 37308559

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Project description:Microtubules play critical roles in regulating the activation of NLRP3 inflammasome and microtubule-destabilizing agents such as colchicine have been shown to suppress the activation of this inflammasome. However, it remains largely unknown whether paclitaxel, a microtubule-stabilizing agent being used in cancer therapy, has any influences on NLRP3 inflammasome activation. Here we showed that paclitaxel pre-treatment greatly enhanced ATP- or nigericin-induced NLRP3 inflammasome activation as indicated by increased release of cleaved caspase-1 and mature IL-1β, enhanced formation of ASC speck, and increased gasdermin D cleavage and pyroptosis. Paclitaxel time- and dose-dependently induced α-tubulin acetylation in LPS-primed murine and human macrophages and further increased ATP- or nigericin-induced α-tubulin acetylation. Such increased α-tubulin acetylation was significantly suppressed either by resveratrol or NAD+ (coenzyme required for deacetylase activity of SIRT2), or by genetic knockdown of MEC-17 (gene encoding α-tubulin acetyltransferase 1). Concurrently, the paclitaxel-mediated enhancement of NLRP3 inflammasome activation was significantly suppressed by resveratrol, NAD+, or MEC-17 knockdown, indicating the involvement of paclitaxel-induced α-tubulin acetylation in the augmentation of NLRP3 inflammasome activation. Similar to paclitaxel, epothilone B that is another microtubule-stabilizing agent also induced α-tubulin acetylation and increased NLRP3 inflammasome activation in macrophages in response to ATP treatment. Consistent with the in vitro results, intraperitoneal administration of paclitaxel significantly increased serum IL-1β levels, reduced bacterial burden, dampened infiltration of inflammatory cells in the liver, and improved animal survival in a mouse model of bacterial infection. Collectively, our data indicate that paclitaxel potentiated NLRP3 inflammasome activation by inducing α-tubulin acetylation and thereby conferred enhanced antibacterial innate responses, suggesting its potential application against pathogenic infections beyond its use as a chemotherapeutic agent.

Dataset Information

A subpopulation of CD146⁺ macrophages enhances antitumor immunity by activating the NLRP3 inflammasome.

Publications

A subpopulation of CD146<sup>+</sup> macrophages enhances antitumor immunity by activating the NLRP3 inflammasome.

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Dataset Information

A subpopulation of CD146+ macrophages enhances antitumor immunity by activating the NLRP3 inflammasome.

Publications

A subpopulation of CD146<sup>+</sup> macrophages enhances antitumor immunity by activating the NLRP3 inflammasome.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

A subpopulation of CD146⁺ macrophages enhances antitumor immunity by activating the NLRP3 inflammasome.