PolyADP-Ribosylation of NFATc3 and NF-κB Transcription Factors Modulate Macrophage Inflammatory Gene Expression in LPS-Induced Acute Lung Injury

• Main Authors: Yunjuan Nie (Author), Teja Srinivas Nirujogi (Author), Ravi Ranjan (Author), Brenda F. Reader (Author), Sangwoon Chung (Author), Megan N. Ballinger (Author), Joshua A. Englert (Author), John W. Christman (Author), Manjula Karpurapu (Author)
• Format: Book
• Published: Karger Publishers, 2020-10-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 1662-811X; 1662-8128; 10.1159/000510269
• Keywords: macrophage; polyadp-ribose polymerase 1; nfatc3; acute lung injury; pulmonary edema; Medicine; R; Internal medicine; RC31-1245
• Source: Journal of Innate Immunity, Pp 1-11 (2020)

Pulmonary macrophages play a critical role in the recognition of pathogens, initiation of host defense via inflammation, clearance of pathogens from the airways, and resolution of inflammation. Recently, we have shown a pivotal role for the nuclear factor of activated T-cell cytoplasmic member 3 (NFATc3) transcription factor in modulating pulmonary macrophage function in LPS-induced acute lung injury (ALI) pathogenesis. Although the NFATc proteins are activated primarily by calcineurin-dependent dephosphorylation, here we show that LPS induces posttranslational modification of NFATc3 by polyADP-ribose polymerase 1 (PARP-1)-mediated polyADP-ribosylation. ADP-ribosylated NFATc3 showed increased binding to iNOS and TNFα promoter DNA, thereby increasing downstream gene expression. Inhibitors of PARP-1 decreased LPS-induced NFATc3 ribosylation, target gene promoter binding, and gene expression. LPS increased NFAT luciferase reporter activity in lung macrophages and lung tissue that was inhibited by pretreatment with PARP-1 inhibitors. More importantly, pretreatment of mice with the PARP-1 inhibitor olaparib markedly decreased LPS-induced cytokines, protein extravasation in bronchoalveolar fluid, lung wet-to-dry ratios, and myeloperoxidase activity. Furthermore, PARP-1 inhibitors decreased NF-кB luciferase reporter activity and LPS-induced ALI in NF-кB reporter mice. Thus, our study demonstrates that inhibiting NFATc3 and NF-кB polyADP-ribosylation with PARP-1 inhibitors prevented LPS-induced ALI pathogenesis.