Dataset Information

Tristetraprolin Overexpression in Non-hematopoietic Cells Protects Against Acute Lung Injury in Mice.

ABSTRACT: Tristetraprolin (TTP) is a mRNA binding protein that binds to adenylate-uridylate-rich elements within the 3' untranslated regions of certain transcripts, such as tumor necrosis factor (Tnf) mRNA, and increases their rate of decay. Modulation of TTP expression is implicated in inflammation; however, its role in acute lung inflammation remains unknown. Accordingly, we tested the role of TTP in lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. LPS-challenged TTP-knockout (TTPKO) mice, as well as myeloid cell-specific TTP-deficient (TTPmyeKO) mice, exhibited significant increases in lung injury, although these responses were more robust in the TTPKO. Mice with systemic overexpression of TTP (TTP?ARE) were protected from ALI, as indicated by significantly reduced neutrophilic infiltration, reduced levels of neutrophil chemoattractants, and histological parameters of ALI. Interestingly, while irradiated wild-type (WT) mice reconstituted with TTPKO hematopoietic progenitor cells (HPCs) showed exaggerated ALI, their reconstitution with the TTP?ARE HPCs mitigated ALI. The reconstitution of irradiated TTP?ARE mice with HPCs from either WT or TTP?ARE donors conferred significant protection against ALI. In contrast, irradiated TTP?ARE mice reconstituted with TTPKO HPCs had exaggerated ALI, but the response was milder as compared to WT recipients that received TTPKO HPCs. Finally, the reconstitution of irradiated TTPKO recipient mice with TTP?ARE HPCs did not confer any protection to the TTPKO mice. These data together suggest that non-HPCs-specific overexpression of TTP within the lungs protects against ALI via downregulation of neutrophil chemoattractants and reduction in neutrophilic infiltration.

SUBMITTER: Choudhary I

PROVIDER: S-EPMC7493631 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Tristetraprolin Overexpression in Non-hematopoietic Cells Protects Against Acute Lung Injury in Mice.

Choudhary Ishita I Vo Thao T Bathula Chandra S CS Lamichhane Richa R Lewis Brandon W BW Looper Jayme J Jeyaseelan Samithamby S Blackshear Perry J PJ Saini Yogesh Y Patial Sonika S

Frontiers in immunology 20200902

Tristetraprolin (TTP) is a mRNA binding protein that binds to adenylate-uridylate-rich elements within the 3' untranslated regions of certain transcripts, such as tumor necrosis factor (<i>Tnf</i>) mRNA, and increases their rate of decay. Modulation of TTP expression is implicated in inflammation; however, its role in acute lung inflammation remains unknown. Accordingly, we tested the role of TTP in lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. LPS-challenged TTP-knockout (TT ...[more]

PMID: 32983182

Similar Datasets

Project description:ObjectiveInflammation and oxidative stress contribute to the progression of sepsis-induced acute lung injury (ALI). SAM domain, SH3 domain and nuclear localization signals 1 (SAMSN1) is a signaling adaptor protein, and mainly regulates inflammatory response of various immune cells. The present study generates macrophage-specific SAMSN1-knockout (Samsn1MKO) and SAMSN1-transgenic (Samsn1MTG) mice to investigate its role and mechanism in sepsis-induced ALI.MethodsSamsn1MKO and Samsn1MTG mice were exposed to lipopolysaccharide (LPS) instillation or cecal ligation and puncture (CLP) surgery to induce sepsis-induced ALI. Bone marrow transplantation, cellular depletion and non-invasive adoptive transfer of bone marrow-derived macrophages (BMDMs) were performed to validate the role of macrophage SAMSN1 in sepsis-induced ALI in vivo. Meanwhile, BMDMs were isolated from Samsn1MKO or Samsn1MTG mice to further clarify the role of SAMSN1 in vitro.ResultsMacrophage SAMSN1 expression was increased in response to LPS stimulation, and negatively correlated with LPS-induced ALI in mice. Macrophage SAMSN1 deficiency exacerbated, while macrophage SAMSN1 overexpression ameliorated LPS-induced inflammation, oxidative stress and ALI in mice and in BMDMs. Mechanistically, we found that macrophage SAMSN1 overexpression prevented LPS-induced ALI though activating AMP-activated protein kinase α2 (AMPKα2) in vivo and in vitro. Further studies revealed that SAMSN1 directly bound to growth factor receptor bound protein 2-associated protein 1 (GAB1) to prevent its protein degradation, and subsequently enhanced protein kinase A (PKA)/AMPKα2 activation in a protein tyrosine phosphatase, non-receptor type 11 (PTPN11, also known as SHP2)-dependent manner. Moreover, we observed that macrophage SAMSN1 overexpression diminished CLP-induced ALI in mice.ConclusionOur study documents the protective role of macrophage SAMSN1 against sepsis-induced inflammation, oxidative stress and ALI through activating AMPKα2 in a GAB1/SHP2/PKA pathway, and defines it as a promising biomarker and therapeutic target to treat sepsis-induced ALI.

Dataset Information

Tristetraprolin Overexpression in Non-hematopoietic Cells Protects Against Acute Lung Injury in Mice.

Publications

Tristetraprolin Overexpression in Non-hematopoietic Cells Protects Against Acute Lung Injury in Mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets