Transcellular delivery of vesicular SOCS proteins from macrophages to epithelial cells blunts inflammatory signaling.
Bottom Line: Secretion is tunable and occurs both in vitro and in vivo.SOCS secretion into lung lining fluid was diminished by cigarette smoking in humans and mice.Secretion and transcellular delivery of vesicular SOCS proteins thus represent a new model for the control of inflammatory signaling, which is subject to dysregulation during states of inflammation.
Affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Department of Microbiology and Immunology, University of Michigan Medical School; and Department of Environmental Health Sciences, School of Public Health; University of Michigan, Ann Arbor, MI 48109.Show MeSH
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Mentions: We found SOCS3 secretion to be unassociated with LDH release (not depicted), arguing against it being a manifestation of cytotoxicity. In addition, it was markedly reduced at 4°C, suggesting that it is an energy-dependent phenomenon (Fig. 2 A). To confirm that SOCS3 is indeed released by AMs through unconventional secretion, we tested the effects of monensin, an inhibitor of conventional secretion. As expected, monensin inhibited rat AM secretion of the known conventionally secreted protein TNF (Fig. 2 B, left); in contrast, it increased secretion of SOCS3 (Fig. 2 B, right), as it has previously been recognized to do for other unconventionally secreted proteins (Rubartelli et al., 1990). Similar results were obtained using brefeldin A, another inhibitor of conventional secretion (not depicted). Unconventional secretion can be vesicular in nature; the finding that SOCS3 in AM-derived CM was more sensitive to proteolysis in the presence of a detergent (Fig. 2 C) implied its packaging within a membranous structure, such as an extracellular vesicle.
Affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Department of Microbiology and Immunology, University of Michigan Medical School; and Department of Environmental Health Sciences, School of Public Health; University of Michigan, Ann Arbor, MI 48109.