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 (TTPΔARE) 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 TTPΔARE HPCs mitigated ALI. The reconstitution of irradiated TTPΔARE mice with HPCs from either WT or TTPΔARE donors conferred significant protection against ALI. In contrast, irradiated TTPΔARE 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 TTPΔARE 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.
Highlights
Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are serious health concerns due to a high rate of mortality [1]
In order to explore the role of TTP in ALI, TTPKO and littermate control WT mice were subjected to ALI through oropharyngeal aspiration of endotoxin (LPS) (Single dose; 10 μg LPS/mouse) for a period of 72 h
These increases were associated with an increased injury to the pulmonary vascular barrier, as depicted by the presence of red blood cells in the cytospins prepared from the bronchoalveolar lavage fluid (BALF) fluid of TTPKO mice (Figure 1E; right panel, black arrow) versus control LPS-challenged WT mice (Figure 1E; left panel)
Summary
Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are serious health concerns due to a high rate of mortality [1]. Germline TTP-knockout (TTPKO) mice exhibit the spontaneous development of a systemic inflammatory syndrome characterized by cachexia, erosive arthritis, myeloid hyperplasia, dermatitis, conjunctivitis, and autoimmunity [4] These phenotypes were shown to be essentially completely prevented in TTPKO mice with either TNF receptor deficiency, or when TTPKO mice were treated with anti-TNF antibodies [5]. TTP ARE mice lack AREs in the 3 UTR of the endogenous TTP gene (Zfp36) that results in increased stability of TTP mRNA and, in turn, moderately increased expression of TTP protein in essentially all the tissues [15] Together, these studies have indicated that TTP may be an endogenous anti-inflammatory protein and that enhancing its levels may be beneficial against various chronic inflammatory diseases
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