The LRP1-independent mechanism of PAI-1-induced migration in CpG-ODN activated macrophages.
CpG-oligodeoxynucleotides (CpG-ODNs) induces plasminogen activator inhibitor type-1 (PAI-1) expression in macrophages, leading to enhanced migration through vitronectin. However, the precise role of low-density lipoprotein receptor-related protein 1 (LRP1) in PAI-1 induced migration of macrophages in the inflammatory environment is not known. In this study, we elucidated a novel mechanism describing the altered role of LRP1 in macrophage migration depending on the activation state of the cells. Experimental evidence clearly shows that the blocking of LRP1 function inhibited the PAI-induced migration of resting RAW 264.7 cells through vitronectin but exerted a pro-migratory effect on CpG-ODN-activated cells. We also demonstrate that CpG-ODN downregulates the protein and mRNA levels of LRP1 both in vivo and in vitro, a function that depends on the NF-κB signaling pathway, resulting in reduced internalization of PAI-1. This work illustrates the distinct mechanism that PAI-1-induced migration of CpG-ODN-activated cells through vitronectin depends on the interaction of PAI-1 with vitronectin but not LRP1 unlike in the resting cells, where the migration is LRP1 dependent and vitronectin independent. In conclusion, our experimental results demonstrate the altered function of LRP1 in the migration of resting and activated macrophages in the context of microenvironmental extracellular matrix components.
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 134 Sinchon-Dong Seodaemun-Gu, 120-749 Seoul, Republic of Korea.
Bikash
B
Thapa
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 134 Sinchon-Dong Seodaemun-Gu, 120-749 Seoul, Republic of Korea.
Yeon Hyang
YH
Kim
Department of Microbiology, College of Medicine, Hallym University, Gangwon-do 200-702, Republic of Korea.
Hyung-Joo
HJ
Kwon
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 134 Sinchon-Dong Seodaemun-Gu, 120-749 Seoul, Republic of Korea. Electronic address: dskim@yonsei.ac.kr.
Doo-Sik
DS
Kim
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D004705:Endocytosis / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051217:Toll-Like Receptor 9 / Q000172:deficiency / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D019096:Vitronectin / Q000378:metabolism / Q000494:pharmacology
C408982:CPG-oligonucleotide; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D017395:Plasminogen Activator Inhibitor 1; D011973:Receptors, LDL; D051217:Toll-Like Receptor 9; D025521:Tumor Suppressor Proteins; D019096:Vitronectin
CpG-ODN; LRP1; Macrophages; Migration; PAI-1