Wang, S.; Zhang, K.; Song, X.; Huang, Q.; Lin, S.; Deng, S.; Qi, M.; Yang, Y.; Lu, Q.; Zhao, D.; Meng, F.; Li, J.; Lian, Z.; Luo, C.; Yao, Y. TLR4 Overexpression Aggravates Bacterial Lipopolysaccharide-Induced Apoptosis via Excessive Autophagy and NF-κB/MAPK Signaling in Transgenic Mammal Models. Cells2023, 12, 1769.
Wang, S.; Zhang, K.; Song, X.; Huang, Q.; Lin, S.; Deng, S.; Qi, M.; Yang, Y.; Lu, Q.; Zhao, D.; Meng, F.; Li, J.; Lian, Z.; Luo, C.; Yao, Y. TLR4 Overexpression Aggravates Bacterial Lipopolysaccharide-Induced Apoptosis via Excessive Autophagy and NF-κB/MAPK Signaling in Transgenic Mammal Models. Cells 2023, 12, 1769.
Wang, S.; Zhang, K.; Song, X.; Huang, Q.; Lin, S.; Deng, S.; Qi, M.; Yang, Y.; Lu, Q.; Zhao, D.; Meng, F.; Li, J.; Lian, Z.; Luo, C.; Yao, Y. TLR4 Overexpression Aggravates Bacterial Lipopolysaccharide-Induced Apoptosis via Excessive Autophagy and NF-κB/MAPK Signaling in Transgenic Mammal Models. Cells2023, 12, 1769.
Wang, S.; Zhang, K.; Song, X.; Huang, Q.; Lin, S.; Deng, S.; Qi, M.; Yang, Y.; Lu, Q.; Zhao, D.; Meng, F.; Li, J.; Lian, Z.; Luo, C.; Yao, Y. TLR4 Overexpression Aggravates Bacterial Lipopolysaccharide-Induced Apoptosis via Excessive Autophagy and NF-κB/MAPK Signaling in Transgenic Mammal Models. Cells 2023, 12, 1769.
Abstract
Gram-negative bacterial infections pose a significant threat to public health. Toll-like receptor 4 (TLR4) recognizes bacterial lipopolysaccharide (LPS) and induces innate immune responses, autophagy and cell death, which have major impacts on the body physiological homeostasis. However, the role of TLR4 in bacterial LPS-induced autophagy and apoptosis in large mammals remains unknown, which are closer to humans than rodents in many physiological characteristics. So far, few reports focus on the relationship between TLR, autophagy and apoptosis in large mammal levels. We urgently need more tools to further explore their crosstalk. Here, we generated a TLR4-enriched mammal model (sheep) and found that a high-dose LPS treatment blocked autophagic degradation and caused strong innate immune responses and severe apoptosis in PBMCs of transgenic offspring. Excessive accumulation of autophagosomes/autolysosomes might contribute to LPS-induced apoptosis in PBMCs of transgenic animals. Further study demonstrated that inhibiting TLR4 downstream NF-κB or p38 MAPK signaling pathways reversed the LPS-induced autophagy activity and apoptosis. These results indicate that the elevated TLR4 aggravates LPS-induced PBMCs apoptosis by leading to lysosomal dysfunction and impaired autophagic flux, which is associated with TLR4 downstream NF-κB and MAPK signaling pathways. This study provides a novel TLR4-enriched mammal model to study its potential effects on autophagy activity, inflammation, oxidative stress and cell death. These findings also enriched the biological functions of TLR4 and provided powerful evidence for bacterial infection.
Biology and Life Sciences, Animal Science, Veterinary Science and Zoology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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