Ror2-mediated cholesterol accumulation regulates autophagic activity within BCG-infected macrophages

Zheng, Xuedi; Li, Mengyuan; Chen, Qi; Ma, Boli; Nie, Xueyi; Liu, Yueyang; Yang, Yi; Xu, Jinrui; Wang, Yujiong

doi:10.1016/j.micpath.2022.105564

Cited by 6 publications

(3 citation statements)

References 44 publications

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“…In contrast, overexpression of ABCG1 in macrophages through lentiviral transduction can significantly reverse foam cell formation ( 52 ). Researchers have constructed a macrophage model infected with Bacille Calmette-Guérin (BCG) and found that BCG infection inhibit the expression of macrophage ABCG1, ABCA1, and ABCA5, promoting intracellular cholesterol accumulation and further inducing macrophage autophagy to suppress BCG infection ( 53 ). Further animal experiments have provided more compelling evidence, as it was found that the expression of ABCA1 and ABCG1, which are involved in cholesterol efflux, was significantly down-regulated in peritoneal macrophages and lung tissue sections of mice infected with H37Ra ( 7 ).…”

Section: The Effect Of Mtb Infection On Macrophage Cholesterol Metabo...mentioning

confidence: 99%

The impact of Mycobacterium tuberculosis on the macrophage cholesterol metabolism pathway

Chen,

Kong,

et al. 2024

Front. Immunol.

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Mycobacterium tuberculosis (Mtb) is an intracellular pathogen capable of adapting and surviving within macrophages, utilizing host nutrients for its growth and replication. Cholesterol is the main carbon source during the infection process of Mtb. Cholesterol metabolism in macrophages is tightly associated with cell functions such as phagocytosis of pathogens, antigen presentation, inflammatory responses, and tissue repair. Research has shown that Mtb infection increases the uptake of low-density lipoprotein (LDL) and cholesterol by macrophages, and enhances de novo cholesterol synthesis in macrophages. Excessive cholesterol is converted into cholesterol esters, while the degradation of cholesterol esters in macrophages is inhibited by Mtb. Furthermore, Mtb infection suppresses the expression of ATP-binding cassette (ABC) transporters in macrophages, impeding cholesterol efflux. These alterations result in the massive accumulation of cholesterol in macrophages, promoting the formation of lipid droplets and foam cells, which ultimately facilitates the persistent survival of Mtb and the progression of tuberculosis (TB), including granuloma formation, tissue cavitation, and systemic dissemination. Mtb infection may also promote the conversion of cholesterol into oxidized cholesterol within macrophages, with the oxidized cholesterol exhibiting anti-Mtb activity. Recent drug development has discovered that reducing cholesterol levels in macrophages can inhibit the invasion of Mtb into macrophages and increase the permeability of anti-tuberculosis drugs. The development of drugs targeting cholesterol metabolic pathways in macrophages, as well as the modification of existing drugs, holds promise for the development of more efficient anti-tuberculosis medications.

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Section: The Effect Of Mtb Infection On Macrophage Cholesterol Metabo...mentioning

confidence: 99%

The impact of Mycobacterium tuberculosis on the macrophage cholesterol metabolism pathway

Chen,

Kong,

et al. 2024

Front. Immunol.

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“…THP-1 cells were maintained in RPMI-1640 medium contained with 10% FBS in a 5% CO 2 incubator at 37 • C. THP-1 cells were seeded into a six-well plate at 1.0 × 10 6 cells/well and stimulated with 50 ng/mL PMA for 48 h to differentiate into macrophages [46]. BCG culture was performed based on a previously described method [47]. After reaching 80-90% confluence, the THP-1 macrophages were infected with BCG at 10 multiplicities of infection (MOI) for 2, 6, 12, 24, and 48 h. In the co-treatment experiment, THP-1 macrophages were pretreated with PERK inhibitor GSK2656157 (5 µM) for 2 h before BCG infection.…”

Section: Thp-1 Cell Culture and Bcg Infectionmentioning

confidence: 99%

GSK2656157, a PERK Inhibitor, Alleviates Pyroptosis of Macrophages Induced by Mycobacterium Bacillus Calmette–Guerin Infection

Ma,

Nie,

Liu

et al. 2023

IJMS

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Tuberculosis (TB) is the leading cause of human death worldwide due to Mycobacterium tuberculosis (Mtb) infection. Mtb infection can cause macrophage pyroptosis. PERK, as a signaling pathway protein on the endoplasmic reticulum, plays an important role in infectious diseases. It is not clear whether PERK is involved in the regulation of pyroptosis of macrophages during Mtb infection. In this study, Bacillus Calmette–Guerin (BCG) infection resulted in high expression of pro-caspase-1, caspase-1 p20, GSDMD-N, and p-PERK in the THP-1 macrophage, being downregulated with the pre-treatment of GSK2656157, a PERK inhibitor. In addition, GSK2656157 inhibited the secretion of IL-1β and IL-18, cell content release, and cell membrane rupture, as well as the decline in cell viability induced by BCG infection. Similarly, GSK2656157 treatment downregulated the expressions of pro-caspase-1, caspase-1 p20, caspase-11, IL-1β p17, IL-18 p22, GSDMD, GSDMD-N, and p-PERK, as well as reducing fibrous tissue hyperplasia, inflammatory infiltration, and the bacterial load in the lung tissue of C57BL/6J mice infected with BCG. In conclusion, the inhibition of PERK alleviated pyroptosis induced by BCG infection, which has an effect of resisting infection.

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“…As intracellular bacteria, Mtb can inhibit or evade innate and adaptive immunity through a variety of strategies. Macrophages can also defend against Mtb infection by initiating programmed cell death, such as apoptosis and autophagy [ 6 , 7 , 8 , 9 ]. In recent years, some research studies have indicated that macrophage pyroptosis plays an extraordinary role in defending against invasion by Mtb [ 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

S100A4 Promotes BCG-Induced Pyroptosis of Macrophages by Activating the NF-κB/NLRP3 Inflammasome Signaling Pathway

Liu

Nie

et al. 2023

IJMS

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Pyroptosis is a host immune strategy to defend against Mycobacterium tuberculosis (Mtb) infection. S100A4, a calcium-binding protein that plays an important role in promoting cancer progression as well as the pathophysiological development of various non-tumor diseases, has not been explored in Mtb-infected hosts. In this study, transcriptome analysis of the peripheral blood of patients with pulmonary tuberculosis (PTB) revealed that S100A4 and GSDMD were significantly up-regulated in PTB patients’ peripheral blood. Furthermore, there was a positive correlation between the expression of GSDMD and S100A4. KEGG pathway enrichment analysis showed that differentially expressed genes between PTB patients and healthy controls were significantly related to inflammation, such as the NOD-like receptor signaling pathway and NF-κB signaling pathway. To investigate the regulatory effects of S100A4 on macrophage pyroptosis, THP-1 macrophages infected with Bacillus Calmette-Guérin (BCG) were pre-treated with exogenous S100A4, S100A4 inhibitor or si-S100A4. This research study has shown that S100A4 promotes the pyroptosis of THP-1 macrophages caused by BCG infection and activates NLRP3 inflammasome and NF-κB signaling pathways, which can be inhibited by knockdown or inhibition of S100A4. In addition, inhibition of NF-κB or NLRP3 blocks the promotion effect of S100A4 on BCG-induced pyroptosis of THP-1 macrophages. In conclusion, S100A4 activates the NF-κB/NLRP3 inflammasome signaling pathway to promote macrophage pyroptosis induced by Mtb infection. These data provide new insights into how S100A4 affects Mtb-induced macrophage pyroptosis.

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Ror2-mediated cholesterol accumulation regulates autophagic activity within BCG-infected macrophages

Cited by 6 publications

References 44 publications

The impact of Mycobacterium tuberculosis on the macrophage cholesterol metabolism pathway

The impact of Mycobacterium tuberculosis on the macrophage cholesterol metabolism pathway

GSK2656157, a PERK Inhibitor, Alleviates Pyroptosis of Macrophages Induced by Mycobacterium Bacillus Calmette–Guerin Infection

S100A4 Promotes BCG-Induced Pyroptosis of Macrophages by Activating the NF-κB/NLRP3 Inflammasome Signaling Pathway

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