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Vimentin is secreted by activated macrophages

Abstract

Vimentin is a widely expressed intermediate filament protein thought to be involved mainly in structural processes, such as wound healing1. We now demonstrate that activated human macrophages secrete vimentin into the extracellular space. The maturation of blood-derived monocytes into macrophages involves several signalling pathways2,3. We show that secretion of vimentin, which is phosphorylated at serine and threonine residues, is enhanced by the phosphatase inhibitor okadaic acid and blocked by the specific protein kinase C inhibitor GÖ6983. These findings are consistent with previous observations that phosphorylation of vimentin affects its intracellular localization and that vimentin is a substrate for protein kinase C (PKC)4,5. We also show that the anti-inflammatory cytokine interleukin-10 (IL-10), which inhibits PKC activity, blocks secretion of vimentin. In contrast, the pro-inflammatory cytokine tumour necrosis factor α (TNF-α) can trigger secretion of vimentin. Finally, we found that extracellular vimentin is involved in bacterial killing and the generation of oxidative metabolites, two important functions of activated macrophages. These data establish that vimentin is secreted by macrophages in response to pro-inflammatory signalling pathways and is probably involved in immune function.

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Figure 1: Localization of vimentin in human MDMs.
Figure 2: Vimentin is secreted in a specific and time-dependent manner.
Figure 3: Vimentin is phosphorylated by the PKC pathway.
Figure 4: Vimentin secretion is modulated by cytokines.

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Acknowledgements

We thank S. Weiss and B. Lane for technical advice and intellectual support, B. Donohoe for help in generating the microscopic images, M. Swanson for help with the phagocytosis assay and J. Cleary for advice on the manuscript. This work was supported by grants to D.M.M. from the American Cancer Society and the Arthritis Foundation, the Rheumatic Disease Core Center of the University of Michigan (5 P30 AR48310-02) and the General Clinical Research Center at the University of Michigan (M01-RR00042). N.M.-V. was supported by a grant from the Arthritis Foundation. A.P. was supported by Merit Review funding and a Research Enhancement Awards Program (REAP) grant from the Department of Veterans Affairs.

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Correspondence to David M. Markovitz.

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We have filed a patent application on the role of secreted vimentin in immunity.

Supplementary information

Supplementary Figures and Table

Figure S1. Vimentin is secreted via the classical ER/Golgi pathway. (PDF 807 kb)

Figure S2. The specificity of vimentin antibodies.

Figure S3. Vimentin is phosphorylated on serine/threonine residues.

Table 1. Isolation and partial amino acid sequence analysis of vimentin from the supernatant of MDM

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Mor-Vaknin, N., Punturieri, A., Sitwala, K. et al. Vimentin is secreted by activated macrophages. Nat Cell Biol 5, 59–63 (2003). https://doi.org/10.1038/ncb898

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