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: Macrophage adherence to plastic culture dishes is recognized to trigger a burst of activation (Kelley et al., 1987). We found that adherence resulted in a rapid burst of release of both SOCS3 (Fig. 5 A, top) as well as MPs (quantified by flow cytometry; Fig. 5 A, bottom), followed by a much lower basal rate of secretion after adherence. SOCS3 secretion increased as early as 5 min after AM adherence (Fig. 5 B). The rapidity of this response is consistent with the known kinetics of MP release described for monocytes (MacKenzie et al., 2001). We next sought to determine whether AM secretion of SOCS proteins could be regulated by known immunomodulatory molecules. The lipid mediator PGE2 down-regulates many features of AM activation (Aronoff et al., 2004; Bourdonnay et al., 2012), and the cytokine IL-10 is well known for its antiinflammatory and immunosuppressive actions (Sabat et al., 2010); these are of particular interest because both are known to be secreted by AECs (Chauncey et al., 1988; Jose et al., 2009) and thus could potentially mediate communication from AECs to AMs. Both rapidly potentiated basal secretion of SOCS3 when added during the post-adherence phase (Fig. 5, C and D), and PGE2 also increased secretion of SOCS1 (not depicted). In contrast, the proinflammatory endotoxin LPS decreased basal SOCS3 secretion in AMs (Fig. 5 D). Unlike the effects of cell adherence (Fig. 5 A), the ability of these immunomodulatory substances to rapidly increase (IL-10 and PGE2) or decrease (LPS) SOCS3 secretion by cultured AMs was unassociated with changes in the number of MPs secreted (Fig. 5 E, left), indicating instead an alteration in the content of SOCS packaged per MP (Fig. 5 E, right).
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.