Affiliation:
1. Division of Cardiology Department of Medicine Emory University Atlanta GA
2. Department of Cardiovascular Medicine Xiangya HospitalCentral South University Changsha China
Abstract
Background
Lung injury, a severe adverse outcome of lipopolysaccharide‐induced acute respiratory distress syndrome, is attributed to excessive neutrophil recruitment and effector response. Poldip2 (polymerase δ‐interacting protein 2) plays a critical role in regulating endothelial permeability and leukocyte recruitment in acute inflammation. Thus, we hypothesized that
myeloid
Poldip2 is involved in neutrophil recruitment to inflamed lungs.
Methods and Results
After characterizing myeloid‐specific
Poldip2
knockout mice, we showed that at 18 hours post‐lipopolysaccharide injection, bronchoalveolar lavage from myeloid Poldip2‐deficient mice contained fewer inflammatory cells (8 [4–16] versus 29 [12–57]×10
4
/mL in wild‐type mice) and a smaller percentage of neutrophils (30% [28%–34%] versus 38% [33%–41%] in wild‐type mice), while the main chemoattractants for neutrophils remained unaffected. In vitro, Poldip2‐deficient neutrophils responded as well as wild‐type neutrophils to inflammatory stimuli with respect to neutrophil extracellular trap formation, reactive oxygen species production, and induction of cytokines. However, neutrophil adherence to a tumor necrosis factor‐α stimulated endothelial monolayer was inhibited by Poldip2 depletion (225 [115–272] wild‐type [myePoldip2
+/+
] versus 133 [62–178] myeloid‐specific
Poldip2
knockout [myePoldip2
‐/‐
] neutrophils) as was transmigration (1.7 [1.3–2.1] versus 1.1 [1.0–1.4] relative to baseline transmigration). To determine the underlying mechanism, we examined the surface expression of β2‐integrin, its binding to soluble intercellular adhesion molecule 1, and Pyk2 phosphorylation. Surface expression of β2‐integrins was not affected by Poldip2 deletion, whereas β2‐integrins and Pyk2 were less activated in Poldip2‐deficient neutrophils.
Conclusions
These results suggest that myeloid Poldip2 is involved in β2‐integrin activation during the inflammatory response, which in turn mediates neutrophil‐to‐endothelium adhesion in lipopolysaccharide‐induced acute respiratory distress syndrome.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
2 articles.
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