1-Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol (PLAG) Rapidly Resolves LPS-Induced Acute Lung Injury Through the Effective Control of Neutrophil Recruitment
Acute lung injury (ALI) is an acute respiratory failure that is associated with excessive neutrophil recruitment and high mortality. To assess the efficacy of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) as a therapeutic agent for ALI, this compound was administered orally to mice challenged...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.02177/full |
| _version_ | 1818985714021302272 |
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| author | Ha-Reum Lee Su-Hyun Shin Su-Hyun Shin Joo Heon Kim Ki-Young Sohn Sun Young Yoon Jae Wha Kim Jae Wha Kim |
| author_facet | Ha-Reum Lee Su-Hyun Shin Su-Hyun Shin Joo Heon Kim Ki-Young Sohn Sun Young Yoon Jae Wha Kim Jae Wha Kim |
| author_sort | Ha-Reum Lee |
| collection | DOAJ |
| description | Acute lung injury (ALI) is an acute respiratory failure that is associated with excessive neutrophil recruitment and high mortality. To assess the efficacy of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) as a therapeutic agent for ALI, this compound was administered orally to mice challenged with an intranasal dose of lipopolysaccharide (LPS). Using this model, we found that PLAG promotes resolution of ALI through effective control of LPS-induced neutrophil infiltration, endothelial permeability, and inflammatory chemokine production. In addition, the Toll like Receptor 4 (TLR4) endocytosis/exocytosis cycle was significantly accelerated in Raw 264.7 cells co-treated with PLAG/LPS, as compared to cells treated only with LPS. During this cycle, a PLAG-induced exotoxin clearance pathway was observed to occur through the prompt assembly of nicotinamide adenine dinucleotide phosphate (NADPH) units and production of reactive oxygen species (ROS), which ultimately lead to earlier LPS clearance. We further detected reduced expression, as well as faster return to homeostatic levels, of macrophage inflammatory protein (MIP)-2, in PLAG/LPS- vs. LPS-treated cells. MIP-2 is a main inducer of neutrophil migration that is mainly controlled by interferon regulatory factor 3 (IRF3) activation and is involved in the TLR4 endosomal-signaling pathway. PLAG induced TLR4-mediated TRIF-related adaptor molecules/Toll-interleukin receptor (TIR) domain-containing adaptor protein including interferon (IFN)-β/IRF3 endosomal signaling, leading to rapid association of TRAM/TRIF and TLR4 and earlier IRF3 phosphorylation in PLAG/LPS-treated vs. LPS-treated cells. PLAG specificity was further verified with PLAG analogs and metabolites known to control excessive neutrophil infiltration, suggesting that this acetylated diacylglycerol has a unique biological role in neutrophil motility. Thus, our data indicate that PLAG may represent a potential therapeutic agent for resolution of LPS-induced lung inflammation through effective MIP-2 modulation. |
| first_indexed | 2024-12-20T18:39:17Z |
| format | Article |
| id | doaj.art-de94c596b75a410584ee23deac89ca68 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-20T18:39:17Z |
| publishDate | 2019-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-de94c596b75a410584ee23deac89ca682022-12-21T19:29:51ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-09-011010.3389/fimmu.2019.021774145841-Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol (PLAG) Rapidly Resolves LPS-Induced Acute Lung Injury Through the Effective Control of Neutrophil RecruitmentHa-Reum Lee0Su-Hyun Shin1Su-Hyun Shin2Joo Heon Kim3Ki-Young Sohn4Sun Young Yoon5Jae Wha Kim6Jae Wha Kim7ENZYCHEM Lifesciences, Seoul, South KoreaDivision of Systems Biology and Bioengineering, Cell Factory Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South KoreaDepartment of Functional Genomics, University of Science and Technology, Daejeon, South KoreaDepartment of Pathology, EulJi University School of Medicine, Daejeon, South KoreaENZYCHEM Lifesciences, Seoul, South KoreaENZYCHEM Lifesciences, Seoul, South KoreaDivision of Systems Biology and Bioengineering, Cell Factory Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South KoreaDepartment of Functional Genomics, University of Science and Technology, Daejeon, South KoreaAcute lung injury (ALI) is an acute respiratory failure that is associated with excessive neutrophil recruitment and high mortality. To assess the efficacy of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) as a therapeutic agent for ALI, this compound was administered orally to mice challenged with an intranasal dose of lipopolysaccharide (LPS). Using this model, we found that PLAG promotes resolution of ALI through effective control of LPS-induced neutrophil infiltration, endothelial permeability, and inflammatory chemokine production. In addition, the Toll like Receptor 4 (TLR4) endocytosis/exocytosis cycle was significantly accelerated in Raw 264.7 cells co-treated with PLAG/LPS, as compared to cells treated only with LPS. During this cycle, a PLAG-induced exotoxin clearance pathway was observed to occur through the prompt assembly of nicotinamide adenine dinucleotide phosphate (NADPH) units and production of reactive oxygen species (ROS), which ultimately lead to earlier LPS clearance. We further detected reduced expression, as well as faster return to homeostatic levels, of macrophage inflammatory protein (MIP)-2, in PLAG/LPS- vs. LPS-treated cells. MIP-2 is a main inducer of neutrophil migration that is mainly controlled by interferon regulatory factor 3 (IRF3) activation and is involved in the TLR4 endosomal-signaling pathway. PLAG induced TLR4-mediated TRIF-related adaptor molecules/Toll-interleukin receptor (TIR) domain-containing adaptor protein including interferon (IFN)-β/IRF3 endosomal signaling, leading to rapid association of TRAM/TRIF and TLR4 and earlier IRF3 phosphorylation in PLAG/LPS-treated vs. LPS-treated cells. PLAG specificity was further verified with PLAG analogs and metabolites known to control excessive neutrophil infiltration, suggesting that this acetylated diacylglycerol has a unique biological role in neutrophil motility. Thus, our data indicate that PLAG may represent a potential therapeutic agent for resolution of LPS-induced lung inflammation through effective MIP-2 modulation.https://www.frontiersin.org/article/10.3389/fimmu.2019.02177/fullacute lung injuryneutrophiltransmigrationinflammationPLAGresolution |
| spellingShingle | Ha-Reum Lee Su-Hyun Shin Su-Hyun Shin Joo Heon Kim Ki-Young Sohn Sun Young Yoon Jae Wha Kim Jae Wha Kim 1-Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol (PLAG) Rapidly Resolves LPS-Induced Acute Lung Injury Through the Effective Control of Neutrophil Recruitment Frontiers in Immunology acute lung injury neutrophil transmigration inflammation PLAG resolution |
| title | 1-Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol (PLAG) Rapidly Resolves LPS-Induced Acute Lung Injury Through the Effective Control of Neutrophil Recruitment |
| title_full | 1-Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol (PLAG) Rapidly Resolves LPS-Induced Acute Lung Injury Through the Effective Control of Neutrophil Recruitment |
| title_fullStr | 1-Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol (PLAG) Rapidly Resolves LPS-Induced Acute Lung Injury Through the Effective Control of Neutrophil Recruitment |
| title_full_unstemmed | 1-Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol (PLAG) Rapidly Resolves LPS-Induced Acute Lung Injury Through the Effective Control of Neutrophil Recruitment |
| title_short | 1-Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol (PLAG) Rapidly Resolves LPS-Induced Acute Lung Injury Through the Effective Control of Neutrophil Recruitment |
| title_sort | 1 palmitoyl 2 linoleoyl 3 acetyl rac glycerol plag rapidly resolves lps induced acute lung injury through the effective control of neutrophil recruitment |
| topic | acute lung injury neutrophil transmigration inflammation PLAG resolution |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.02177/full |
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