Cargando…

TLR4 Overexpression Aggravates Bacterial Lipopolysaccharide-Induced Apoptosis via Excessive Autophagy and NF-κB/MAPK Signaling in Transgenic Mammal Models

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’s physiological homeostasis. However, the role...

Descripción completa

Detalles Bibliográficos
Autores principales: Wang, Sutian, Zhang, Kunli, Song, Xuting, Huang, Qiuyan, Lin, Sen, Deng, Shoulong, Qi, Meiyu, Yang, Yecheng, Lu, Qi, Zhao, Duowei, Meng, Fanming, Li, Jianhao, Lian, Zhengxing, Luo, Chenglong, Yao, Yuchang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10340758/
https://www.ncbi.nlm.nih.gov/pubmed/37443803
http://dx.doi.org/10.3390/cells12131769
_version_ 1785072156111011840
author Wang, Sutian
Zhang, Kunli
Song, Xuting
Huang, Qiuyan
Lin, Sen
Deng, Shoulong
Qi, Meiyu
Yang, Yecheng
Lu, Qi
Zhao, Duowei
Meng, Fanming
Li, Jianhao
Lian, Zhengxing
Luo, Chenglong
Yao, Yuchang
author_facet Wang, Sutian
Zhang, Kunli
Song, Xuting
Huang, Qiuyan
Lin, Sen
Deng, Shoulong
Qi, Meiyu
Yang, Yecheng
Lu, Qi
Zhao, Duowei
Meng, Fanming
Li, Jianhao
Lian, Zhengxing
Luo, Chenglong
Yao, Yuchang
author_sort Wang, Sutian
collection PubMed
description 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’s physiological homeostasis. However, the role of TLR4 in bacterial LPS-induced autophagy and apoptosis in large mammals, which are closer to humans than rodents in many physiological characteristics, remains unknown. So far, few reports focus on the relationship between TLR, autophagy, and apoptosis in large mammal levels, and 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 monocytes/macrophages of transgenic offspring. Excessive accumulation of autophagosomes/autolysosomes might contribute to LPS-induced apoptosis in monocytes/macrophages 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 monocytes/macrophages 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 enrich the biological functions of TLR4 and provide powerful evidence for bacterial infection.
format Online
Article
Text
id pubmed-10340758
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-103407582023-07-14 TLR4 Overexpression Aggravates Bacterial Lipopolysaccharide-Induced Apoptosis via Excessive Autophagy and NF-κB/MAPK Signaling in Transgenic Mammal Models Wang, Sutian Zhang, Kunli Song, Xuting Huang, Qiuyan Lin, Sen Deng, Shoulong Qi, Meiyu Yang, Yecheng Lu, Qi Zhao, Duowei Meng, Fanming Li, Jianhao Lian, Zhengxing Luo, Chenglong Yao, Yuchang Cells Article 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’s physiological homeostasis. However, the role of TLR4 in bacterial LPS-induced autophagy and apoptosis in large mammals, which are closer to humans than rodents in many physiological characteristics, remains unknown. So far, few reports focus on the relationship between TLR, autophagy, and apoptosis in large mammal levels, and 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 monocytes/macrophages of transgenic offspring. Excessive accumulation of autophagosomes/autolysosomes might contribute to LPS-induced apoptosis in monocytes/macrophages 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 monocytes/macrophages 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 enrich the biological functions of TLR4 and provide powerful evidence for bacterial infection. MDPI 2023-07-03 /pmc/articles/PMC10340758/ /pubmed/37443803 http://dx.doi.org/10.3390/cells12131769 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wang, Sutian
Zhang, Kunli
Song, Xuting
Huang, Qiuyan
Lin, Sen
Deng, Shoulong
Qi, Meiyu
Yang, Yecheng
Lu, Qi
Zhao, Duowei
Meng, Fanming
Li, Jianhao
Lian, Zhengxing
Luo, Chenglong
Yao, Yuchang
TLR4 Overexpression Aggravates Bacterial Lipopolysaccharide-Induced Apoptosis via Excessive Autophagy and NF-κB/MAPK Signaling in Transgenic Mammal Models
title TLR4 Overexpression Aggravates Bacterial Lipopolysaccharide-Induced Apoptosis via Excessive Autophagy and NF-κB/MAPK Signaling in Transgenic Mammal Models
title_full TLR4 Overexpression Aggravates Bacterial Lipopolysaccharide-Induced Apoptosis via Excessive Autophagy and NF-κB/MAPK Signaling in Transgenic Mammal Models
title_fullStr TLR4 Overexpression Aggravates Bacterial Lipopolysaccharide-Induced Apoptosis via Excessive Autophagy and NF-κB/MAPK Signaling in Transgenic Mammal Models
title_full_unstemmed TLR4 Overexpression Aggravates Bacterial Lipopolysaccharide-Induced Apoptosis via Excessive Autophagy and NF-κB/MAPK Signaling in Transgenic Mammal Models
title_short TLR4 Overexpression Aggravates Bacterial Lipopolysaccharide-Induced Apoptosis via Excessive Autophagy and NF-κB/MAPK Signaling in Transgenic Mammal Models
title_sort tlr4 overexpression aggravates bacterial lipopolysaccharide-induced apoptosis via excessive autophagy and nf-κb/mapk signaling in transgenic mammal models
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10340758/
https://www.ncbi.nlm.nih.gov/pubmed/37443803
http://dx.doi.org/10.3390/cells12131769
work_keys_str_mv AT wangsutian tlr4overexpressionaggravatesbacteriallipopolysaccharideinducedapoptosisviaexcessiveautophagyandnfkbmapksignalingintransgenicmammalmodels
AT zhangkunli tlr4overexpressionaggravatesbacteriallipopolysaccharideinducedapoptosisviaexcessiveautophagyandnfkbmapksignalingintransgenicmammalmodels
AT songxuting tlr4overexpressionaggravatesbacteriallipopolysaccharideinducedapoptosisviaexcessiveautophagyandnfkbmapksignalingintransgenicmammalmodels
AT huangqiuyan tlr4overexpressionaggravatesbacteriallipopolysaccharideinducedapoptosisviaexcessiveautophagyandnfkbmapksignalingintransgenicmammalmodels
AT linsen tlr4overexpressionaggravatesbacteriallipopolysaccharideinducedapoptosisviaexcessiveautophagyandnfkbmapksignalingintransgenicmammalmodels
AT dengshoulong tlr4overexpressionaggravatesbacteriallipopolysaccharideinducedapoptosisviaexcessiveautophagyandnfkbmapksignalingintransgenicmammalmodels
AT qimeiyu tlr4overexpressionaggravatesbacteriallipopolysaccharideinducedapoptosisviaexcessiveautophagyandnfkbmapksignalingintransgenicmammalmodels
AT yangyecheng tlr4overexpressionaggravatesbacteriallipopolysaccharideinducedapoptosisviaexcessiveautophagyandnfkbmapksignalingintransgenicmammalmodels
AT luqi tlr4overexpressionaggravatesbacteriallipopolysaccharideinducedapoptosisviaexcessiveautophagyandnfkbmapksignalingintransgenicmammalmodels
AT zhaoduowei tlr4overexpressionaggravatesbacteriallipopolysaccharideinducedapoptosisviaexcessiveautophagyandnfkbmapksignalingintransgenicmammalmodels
AT mengfanming tlr4overexpressionaggravatesbacteriallipopolysaccharideinducedapoptosisviaexcessiveautophagyandnfkbmapksignalingintransgenicmammalmodels
AT lijianhao tlr4overexpressionaggravatesbacteriallipopolysaccharideinducedapoptosisviaexcessiveautophagyandnfkbmapksignalingintransgenicmammalmodels
AT lianzhengxing tlr4overexpressionaggravatesbacteriallipopolysaccharideinducedapoptosisviaexcessiveautophagyandnfkbmapksignalingintransgenicmammalmodels
AT luochenglong tlr4overexpressionaggravatesbacteriallipopolysaccharideinducedapoptosisviaexcessiveautophagyandnfkbmapksignalingintransgenicmammalmodels
AT yaoyuchang tlr4overexpressionaggravatesbacteriallipopolysaccharideinducedapoptosisviaexcessiveautophagyandnfkbmapksignalingintransgenicmammalmodels