PMID- 26741694 OWN - NLM STAT- MEDLINE DCOM- 20160706 LR - 20190222 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 11 IP - 1 DP - 2016 TI - Toll-Like Receptor 4 Is Essential in the Development of Abdominal Aortic Aneurysm. PG - e0146565 LID - 10.1371/journal.pone.0146565 [doi] LID - e0146565 AB - Toll-like receptor (TLR) family plays a key role in innate immunity and various inflammatory responses. TLR4, one of the well-characterized pattern-recognition receptors, can be activated by endogenous damage-associated molecular pattern molecules such as high mobility group box 1 (HMGB1) to sustain sterile inflammation. Evidence suggested that blockade of TLR4 signaling may confer protection against abdominal aortic aneurysm (AAA). Herein we aimed to obtain further insight into the mechanism by which TLR4 might promote aneurysm formation. Characterization of the CaCl2-induced AAA model in mice revealed that upregulation of TLR4 expression, localized predominantly to vascular smooth muscle cells (VSMCs), was followed by a late decline during a 28-day period of AAA development. In vitro, TLR4 expression was increased in VSMCs treated with HMGB1. Knockdown of TLR4 by siRNA attenuated HMGB1-enhanced production of proinflammatory cytokines, specifically interleukin-6 and monocyte chemoattractant protein-1 (MCP-1), and matrix-degrading matrix metalloproteinase (MMP)-2 from VSMCs. In vivo, two different strains of TLR4-deficient (C57BL/10ScNJ and C3H/HeJ) mice were resistant to CaCl2-induced AAA formation compared to their respective controls (C57BL/10ScSnJ and C3H/HeN). Knockout of TLR4 reduced interleukin-6 and MCP-1 levels and HMGB1 expression, attenuated macrophage accumulation, and eventually suppressed MMP production, elastin destruction and VSMC loss. Finally, human AAA exhibited higher TLR4 expression that was localized to VSMCs. These data suggest that TLR4 signaling contributes to AAA formation by promoting a proinflammatory status of VSMCs and by inducing proteinase release from VSMCs during aneurysm initiation and development. FAU - Lai, Chao-Han AU - Lai CH AD - Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. AD - Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan. FAU - Wang, Kuan-Chieh AU - Wang KC AD - Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan. AD - Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. FAU - Lee, Fang-Tzu AU - Lee FT AD - Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan. AD - Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. FAU - Tsai, Hung-Wen AU - Tsai HW AD - Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. FAU - Ma, Chih-Yuan AU - Ma CY AD - Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan. AD - Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. FAU - Cheng, Tsung-Lin AU - Cheng TL AD - Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan. AD - Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. AD - Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. FAU - Chang, Bi-Ing AU - Chang BI AD - Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan. AD - Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. FAU - Yang, Yu-Jen AU - Yang YJ AD - Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. AD - Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan. FAU - Shi, Guey-Yueh AU - Shi GY AD - Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan. AD - Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. FAU - Wu, Hua-Lin AU - Wu HL AD - Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan. AD - Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160107 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Ager protein, mouse) RN - 0 (Cytokines) RN - 0 (HMGB1 Protein) RN - 0 (HMGB1 protein, mouse) RN - 0 (Receptor for Advanced Glycation End Products) RN - 0 (TLR4 protein, human) RN - 0 (Tlr4 protein, mouse) RN - 0 (Toll-Like Receptor 4) RN - EC 3.4.24.- (Matrix Metalloproteinases) RN - M4I0D6VV5M (Calcium Chloride) SB - IM MH - Animals MH - Aortic Aneurysm, Abdominal/chemically induced/*metabolism MH - Calcium Chloride MH - Case-Control Studies MH - Cells, Cultured MH - Cytokines/biosynthesis MH - HMGB1 Protein/metabolism MH - Humans MH - Male MH - Matrix Metalloproteinases/metabolism MH - Mice, Inbred C3H MH - Mice, Inbred C57BL MH - Muscle, Smooth, Vascular/enzymology MH - Myocytes, Smooth Muscle/enzymology MH - Receptor for Advanced Glycation End Products/metabolism MH - Toll-Like Receptor 4/genetics/metabolism/*physiology MH - Up-Regulation PMC - PMC4711799 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2016/01/08 06:00 MHDA- 2016/07/07 06:00 PMCR- 2016/01/07 CRDT- 2016/01/08 06:00 PHST- 2015/08/23 00:00 [received] PHST- 2015/12/18 00:00 [accepted] PHST- 2016/01/08 06:00 [entrez] PHST- 2016/01/08 06:00 [pubmed] PHST- 2016/07/07 06:00 [medline] PHST- 2016/01/07 00:00 [pmc-release] AID - PONE-D-15-37017 [pii] AID - 10.1371/journal.pone.0146565 [doi] PST - epublish SO - PLoS One. 2016 Jan 7;11(1):e0146565. doi: 10.1371/journal.pone.0146565. eCollection 2016.