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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 (TTP KO ) mice, as well as myeloid cell-specific TTP-deficient (TTP myeKO ) mice, exhibited significant increases in lung injury, although these responses were more robust in the TTP KO . Mice with systemic overexpression of TTP (TTP ΔARE ) 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 TTP KO hematopoietic progenitor cells (HPCs) showed exaggerated ALI, their reconstitution with the TTP ΔARE HPCs mitigated ALI. The reconstitution of irradiated TTP ΔARE mice with HPCs from either WT or TTP ΔARE donors conferred significant protection against ALI. In contrast, irradiated TTP ΔARE mice reconstituted with TTP KO HPCs had exaggerated ALI, but the response was milder as compared to WT recipients that received TTP KO HPCs. Finally, the reconstitution of irradiated TTP KO recipient mice with TTP ΔARE HPCs did not confer any protection to the TTP KO 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., (Copyright © 2020 Choudhary, Vo, Bathula, Lamichhane, Lewis, Looper, Jeyaseelan, Blackshear, Saini and Patial.)