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Publication : Free actin impairs macrophage bacterial defenses via scavenger receptor MARCO interaction with reversal by plasma gelsolin.

First Author  Ordija CM Year  2017
Journal  Am J Physiol Lung Cell Mol Physiol Volume  312
Issue  6 Pages  L1018-L1028
PubMed ID  28385809 Mgi Jnum  J:243302
Mgi Id  MGI:5908071 Doi  10.1152/ajplung.00067.2017
Citation  Ordija CM, et al. (2017) Free actin impairs macrophage bacterial defenses via scavenger receptor MARCO interaction with reversal by plasma gelsolin. Am J Physiol Lung Cell Mol Physiol 312(6):L1018-L1028
abstractText  Lung injury can release intracellular actin into the alveolar milieu and is also associated with increased susceptibility to secondary infections. We investigated the effect of free (extracellular) actin on lung macrophage host defense functions. Western blot analysis demonstrated free actin release into the lung lavage fluids of mouse models of ozone injury, influenza infection, and secondary pneumococcal pneumonia and in samples from patients following burn and inhalation injury. Using levels comparable with those observed in lung injury, we found that free actin markedly inhibited murine lung macrophage binding and uptake in vitro of S. pneumoniae, S. aureus, and E. coli, (e.g., S. pneumoniae, mean %inhibition, actin vs. vehicle: 85 +/- 0.3 (SD); n = 22, P < .001). Similar effects were observed on the ability of primary human macrophages to bind and ingest fluorescent Saureus (~75% inhibition). Plasma gelsolin (pGSN), a protein that functions to bind and cleave actin, restored bacterial binding and uptake by both murine and human macrophages. Scavenger receptor inhibitors reduced binding of fluorescent actin by murine macrophages [fluorescence index (x10-3) after incubation with vehicle, actin, or actin + polyinosinic acid, respectively: 0.8 +/- 0.7, 101.7 +/- 50.7, or 52.7 +/- 16.9; n = 5-6, P < 0.05]. In addition, actin binding was reduced in a MARCO/SR-AI/II-deficient cell line and by normal AMs obtained from MARCO-/- mice. After release from injured cells during lung injury, free actin likely contributes to impaired host defense by blocking scavenger receptor binding of bacteria. This mechanism for increased risk of secondary infections after lung injury or inflammation may represent another target for therapeutic intervention with pGSN.
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