Leukocyte-specific protein 1 regulates neutrophil recruitment in acute lung inflammation

Abstract

The mechanisms of excessive migration of activated neutrophils into inflamed lungs, credited with tissue damage, are not fully understood. We explored the hitherto unknown expression of leukocyte-specific protein 1 (LSP1) in human and mouse lungs and neutrophils and examined its role in neutrophil migration in acute lung inflammation. Autopsied septic human lungs showed increased LSP1 labeling in epithelium, endothelium, and leukocytes, including in their nuclei compared with normal lungs. We induced acute lung inflammation through intranasal administration of E. coli lipopolysaccharide (LPS) (80 μg) in LSP1-deficient (Lsp1(-/-)) and wild-type (WT) 129/SvJ mice. Immunocytochemistry and Western blots showed increased expression of LSP1 and phosphorylated LSP1 in lungs of LPS-treated WT mice. Histology showed more congestion, inflammation, and Gr-1(+) neutrophils in lung of WT mice than Lsp1(-/-) mice. LPS-treated WT mice had significantly more neutrophils in bronchoalveolar lavage (BAL) and myeloperoxidase levels in lungs compared with Lsp1(-/-) mice. However, there were no differences in lung tissue and BAL concentrations of keratinocyte-derived chemokine, monocyte chemoattractant protein-1, macrophage inflammatory protein-1α and -1β, vascular permeability, and phosphorylated p38 MAPK between LPS-treated WT and Lsp1(-/-) mice, whereas TNF-α concentration was higher in BAL fluid from LPS-treated WT. Immunoelectron microscopy showed increased LSP1 in the nuclei of LPS-treated neutrophils. We also found increased levels of phosphorylated LSP1 associated with plasma membrane, nucleus, and cytosol at various times after LPS treatment of murine bone marrow-derived neutrophils, suggesting its role in modulation of neutrophil cytoskeleton and the membrane. These data collectively show increased expression of LSP1 in inflamed mouse and human lungs and its role in neutrophil recruitment and lung inflammation.

Retracted: Lymphocyte‐specific protein 1 inhibits the growth of hepatocellular carcinoma by suppressing ERK1/2 phosphorylation

“…Protein NUPR1 has been identified as a potential therapeutic target in hepatocarcinogenesis, which may contribute to the progression of HCC . LSP1, which is mainly expressed in lymphocytes , neutrophils , macrophages and endothelium , has been reported to be correlated with several kinds of cancers, such as breast cancer , lymphomas , pancreatic cancer and dermatofibroma . Polymorphisms of LSP1 are associated with high risk of breast cancer in women who have an existing mutation of the BRCA1 gene .…”

When Actin is Not Actin’ Like It Should: A New Category of Distinct Primary Immunodeficiency Disorders

“…2). Ena/VASP proteins enhance actin filament elongation and can also bind to the WRC to enhance ARP2/3 complex activity [17]. Furthermore, depolymerization of actin filaments is essential for dynamic actin remodeling and mediated by several regulatory proteins (shown in Fig.…”

“…It has several actin-binding domains in the latter half of the protein, which includes 2 caldesmon-like and villin-headpiece-like domains [214, 215] and on a molecular level it most likely functions by bundling actin filaments [216]. Postmortem samples indicate that LSP1 is upregulated in the epithelium, endothelium, and leukocytes of septic lungs; thus, it seems to play a role during inflammation in these cell types [17].…”

“…Because LSP1 functions as an actin-capping protein, the overexpression of LSP1 probably prevents F-actin formation. The effect of LSP1 overexpression may not be limited to neutrophils but can also affect endothelial and epithelial cells in mouse models [17, 214, 220].…”

Expression Quantitative Trait Methylation Analysis Reveals Methylomic Associations With Gene Expression in Childhood Asthma

“…Most of the top eQTM genes (by eQTM P-value) have been implicated in lung disease (Figure 2). PAX8 is associated with bronchodilator response in children with asthma 4 , ECHDC3 is associated with obesity and asthma in children 5 , LSP1 is associated with acute lung inflammation 6 , HLA-DQB1 is associated with asthma 7 and total IgE 8 , FRG1B is highly mutated in lung adenocarcinoma 9 , and KANSL1 is associated with pulmonary function 10 .…”