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

Abstract

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.

• Authors: Boli Ma, Xueyi Nie, Lei Liu, Mengyuan Li, Qi Chen, Yueyang Liu, Yuxin Hou, Yi Yang, Jinrui Xu
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 24 Issue 22 (Nov 12 2023) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 38003429 (Publication Type: Journal Article)

Chemical References

• GSK2656157
• Interleukin-18
• BCG Vaccine
• Caspase 1
• Caspases

Topics

• Animals
• Mice
• Humans
• Interleukin-18 (metabolism)
• BCG Vaccine
• Caspase 1 (metabolism)
• Pyroptosis
• Mice, Inbred C57BL
• Macrophages (metabolism)
• Mycobacterium bovis (metabolism)
• Caspases (metabolism)