巨噬细胞表面 GAPDH 的调节改变了 LL-37 在细胞中的内化和下游效应。

IF 4.7 3区 医学 Q2 IMMUNOLOGY Journal of Innate Immunity Pub Date : 2023-01-01 Epub Date: 2023-04-20 DOI:10.1159/000530083
Asmita Dhiman, Sharmila Talukdar, Gaurav Kumar Chaubey, Rahul Dilawari, Radheshyam Modanwal, Surbhi Chaudhary, Anil Patidar, Vishant Mahendra Boradia, Pradeep Kumbhar, Chaaya Iyengar Raje, Manoj Raje
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引用次数: 0

摘要

结核分枝杆菌(M.tb)是结核病(TB)的主要致病菌,它已进化出逃避宿主防御和在宿主细胞内存活的机制。针对受感染细胞的宿主定向疗法(HDTs)正成为一种有效的选择。众所周知,阳离子宿主防御肽 LL-37 可以内化到细胞中,诱导自噬,从而在细胞内杀死 M.tb。这种肽还能调节免疫系统,并与巨噬细胞内的多功能蛋白甘油醛-3-磷酸脱氢酶(GAPDH)相互作用。我们的研究发现,GAPDH 是一种单核细胞表面受体,能将 LL-37 内化。我们证实,在感染了 M.tb 的巨噬细胞中,P2X7(之前报道的该肽的受体)的表面水平保持不变。在感染或细胞被 IFNγ 激活后,表面招募的 GAPDH 与 LL-37 结合,并通过脂质筏依赖过程将其内化到内细胞区。我们还发现了 GAPDH 在 LL-37 介导的自噬诱导和清除细胞内病原体中的作用。在 GAPDH 被敲除的受感染巨噬细胞中,我们观察到 LL-37 介导的自噬受到了抑制,而 GAPDH 的过度表达则挽救了这种抑制。这一过程依赖于细胞内钙和 P38 MAPK 通路。我们的研究结果揭示了巨噬细胞通过细胞表面 GAPDH 内化抗菌肽的一个前所未知的过程,并表明 GAPDH 在调节细胞对 LL-37 的表型反应从而减少 M.tb 负担方面发挥着兼职作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Regulation of Macrophage Cell Surface GAPDH Alters LL-37 Internalization and Downstream Effects in the Cell.

Mycobacterium tuberculosis (M.tb), the major causative agent of tuberculosis, has evolved mechanisms to evade host defenses and persist within host cells. Host-directed therapies against infected cells are emerging as an effective option. Cationic host defense peptide LL-37 is known to internalize into cells and induce autophagy resulting in intracellular killing of M.tb. This peptide also regulates the immune system and interacts with the multifunctional protein glyceraldehyde-3-phosphate dehydrogenase (GAPDH) inside macrophages. Our investigations revealed that GAPDH moonlights as a mononuclear cell surface receptor that internalizes LL-37. We confirmed that the surface levels of purinergic receptor 7, the receptor previously reported for this peptide, remained unaltered on M.tb infected macrophages. Upon infection or cellular activation with IFNγ, surface recruited GAPDH bound to and internalized LL-37 into endocytic compartments via a lipid raft-dependent process. We also discovered a role for GAPDH in LL-37-mediated autophagy induction and clearance of intracellular pathogens. In infected macrophages wherein GAPDH had been knocked down, we observed an inhibition of LL-37-mediated autophagy which was rescued by GAPDH overexpression. This process was dependent on intracellular calcium and p38 MAPK pathways. Our findings reveal a previously unknown process by which macrophages internalize an antimicrobial peptide via cell surface GAPDH and suggest a moonlighting role of GAPDH in regulating cellular phenotypic responses of LL-37 resulting in reduction of M.tb burden.

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来源期刊
Journal of Innate Immunity
Journal of Innate Immunity 医学-免疫学
CiteScore
10.50
自引率
1.90%
发文量
35
审稿时长
7.5 months
期刊介绍: The ''Journal of Innate Immunity'' is a bimonthly journal covering all aspects within the area of innate immunity, including evolution of the immune system, molecular biology of cells involved in innate immunity, pattern recognition and signals of ‘danger’, microbial corruption, host response and inflammation, mucosal immunity, complement and coagulation, sepsis and septic shock, molecular genomics, and development of immunotherapies. The journal publishes original research articles, short communications, reviews, commentaries and letters to the editors. In addition to regular papers, some issues feature a special section with a thematic focus.
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