Abstract: TH-PO362

NF-E2 Is Induced in the Lungs of ABIN1-(D485N) Mice

Session Information

Category: Cell Biology

  • 201 Cell Signaling, Oxidative Stress

Authors

  • Powell, David W., University of Louisville, Louisville, Kentucky, United States
  • Rane, Sanjana, University of Louisville, Louisville, Kentucky, United States
  • Jin, Shunying, UNIVERSITY OF LOUISVILLE, LOUISVILLE, Kentucky, United States
  • Korte, Erik, None, Louisville, Kentucky, United States
  • Barati, Michelle T., University of Louisville, Louisville, Kentucky, United States
  • Rane, Madhavi J., University of Louisville, Louisville, Kentucky, United States
Background

Inflammation caused by systemic lupus erythematosus (SLE) can affect the kidneys and lungs. Variants for the ABIN1 gene (TNIP1) are risk factors for glomerulonephritis (GN) in SLE and a knock-in mouse expressing an inactive form of ABIN1-(D485N) spontaneously developed systemic autoimmunity and progressive GN. IL-8 increases in plasma of ABIN1 (D485N) mice, a target of Nuclear Factor-Erythroid derived 2 (NF-E2). Inflammatory mediators in the lungs, bronchoalveolar lavage fluid (BALf), and plasma of WT and ABIN1-(D485N) mice were examined in the current study.

Methods

Three and six month old wild-type (WT) and ABIN1-(D485N) mouse lung homogenates, BALF, and plasma samples were immunoblotted for Myeloperoxidase (MPO), Thrombospondin 1 (TSP1), Nuclear Factor-Erythroid derived 2 (NF-E2) and CRP. Six-month old WT and ABIN1-(D485N) mouse kidneys were also subjected to H&E staining and MPO immunohistochemistry.

Results

Increased pulmonary MPO, TSP1 and NF-E2 expression was detected in 3 m old ABIN1-(D485N) mice. Concurrently, increased TSP-1, NF-E2 and CRP were detected in the plasma of 3 m old ABIN1-(D485N) mice. Cleaved caspase-3 was detected in lungs of ABIN1-(D485N) mice suggesting increased pulmonary apoptosis. In 6 m old ABIN1-(D485N) mice, H&E and MPO staining demonstrated immune cell recruitment in lung tissue sections. CRP and NF-E2 expression persisted in ABIN1-(D485N) mice at 6 m of age. NF-E2 and CRP was detected in the BALf of 6 m old ABIN1-(D485N) mice. To examine the role of NF-E2 in BALf, recombinant purified NF-E2 protein or control vector protein was intratracheally administered to long evans rats and 2 h after administration the rats were sacrificed and BALf, lung homogenates and lung tissue sections were obtained. Neutrophils were recruited into the BALf of rats treated with recombinant NF-E2 but not control protein and H&E staining of tissue demonstrated lung damage. Moreover, recombinant NF-E2 was shown to promote human neutrophil actin polymerization, chemotaxis, and survival.

Conclusion

Thus, an inactive form of ABIN1-(D485N) leads to induction of NF-E2 in the lungs. Neutrophil recruitment in the lungs and ex-vivo activation of neutrophils by recombinant NF-E2 suggests that NF-E2 may serve as a novel immune modulator and a potential therapeutic target.

Funding

  • Other NIH Support