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.

Tuberculosis (TB) is a zoonotic infectious disease caused by Mycobacterium tuberculosis (Mtb). Mtb is a typical intracellular parasite, and macrophages are its main host cells. NLRP3 inflammasome-mediated pyroptosis is a form of programmed cell death implicated in the clearance of pathogenic infections. The bidirectional regulatory effect of endoplasmic reticulum stress (ERS) plays a crucial role in determining cell survival and death. Whether ERS is involved in macrophage pyroptosis with Mtb infection remains unclear. This article aims to explore the regulation of the NLRP3 inflammasome and pyroptosis by ERS in THP-1 macrophages infected with Mycobacterium bovis Bacillus Calmette-Guérin (BCG). The results showed that BCG infection induced THP-1 macrophage ERS, NLRP3 inflammasome activation and pyroptosis, which was inhibited by ERS inhibitor TUDCA. NLRP3 inhibitor MCC950 inhibited THP-1 macrophage NLRP3 inflammasome activation and pyroptosis caused by BCG infection. Compared with specific Caspase-1 inhibitor VX-765, pan-Caspase inhibitor Z-VAD-FMK showed a more significant inhibitory effect on BCG infection-induced pyroptosis of THP-1 macrophages. Taken together, this study demonstrates that ERS mediated NLRP3 inflammasome activation and pyroptosis after BCG infection of THP-1 macrophages, and that BCG infection of THP-1 macrophages induces pyroptosis through canonical and noncanonical pathways.

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.

Identifying the specific factors secreted during early pregnancy is an effective method for pregnancy detection in cattle, helping to reduce empty pregnancies in the industry. To systematically investigate metabolic variations between early pregnancy and the estrous cycle and their relationship with pregnancy progression, this study utilized four-dimensional data-independent acquisition (4D-DIA) proteomics and liquid chromatography–tandem mass spectrometry (LC-MS/MS) metabolomics to analyze serum samples collected from Chinese native yellow cattle at day 0 and day 21 post-mating, combining bioinformatics analysis with experimental validation. The platelet activation signaling pathway and angiogenesis-related proteins were significantly upregulated. Among them, fibrinogen alpha/beta/gamma chains (FG) exhibited notable differences, with their branched-chain protein FGB showing highly significant upregulation (p = 0.003, Log₂FC = 2.167) and tending to increase gradually during early pregnancy, suggesting that FGB could be one of the important indicators of early pregnancy in Chinese native yellow cattle. Among the differential metabolites, 11-Deoxy prostaglandin F1α (p < 0.001, Log₂FC = 1.563), Thromboxane B1 (p = 0.002, Log₂FC = 3.335), and Homo-Gamma-Linolenic Acid (C20:3) (p = 0.018, Log₂FC = 1.781) were also increased, indicating their involvement in the regulation of the platelet activation signaling pathway. The platelet activation signaling pathway plays a crucial role in maternal immune tolerance and placental vascularization, which are essential for embryo implantation and placental development. These findings indicate that FGB has the potential to be a valuable biomarker for early cattle pregnancy detection, thereby improving pregnancy diagnosis accuracy, reducing economic losses caused by undetected empty pregnancies and enhancing reproductive efficiency in the cattle industry. Undoubtedly, our research outcomes must be validated with future studies, and a larger sample size as well as the evaluation of the potential endocrine effects induced by the synchronized estrus treatment must be considered.

Lei Liu was not included as an author in the original publication