Description of Research: Nirit Mor-Vaknin

Autoimmune diseases arise when the immune system turns its antimicrobial defenses upon normal components of the body (self). While the cause of autoimmune disease is not clear, autoimmune diseases affect 5% of the world's population, and there is evidence of increasing disease incidence in children. Our studies focus on the potential new role of nuclear proteins, such as DEK and intracellular intermediate filaments, such as vimentin, in the innate immunity response to bacterial infection and the development of autoimmune diseases.

We recently discovered that the nuclear protein DEK and the cytoskeleton protein vimentin are both actively secreted by human macrophages. Macrophages can secrete many proteins as part of their immune function; proteins such as cytokines, chemokines and proteases. However, the secretion of nuclear proteins or cytoskeleton proteins by macrophages is unusual and may indicate a unique immunological function for both DEK and vimentin.

The intermediate filament vimentin, which is particularly abundant in human macrophages, has always been regarded as an intracellular structural protein. However, vimentin secretion via activated macrophages suggests a whole set of different functions for vimentin. Indeed, we have shown that extracellular vimentin is involved in the generation of oxidative metabolites and the killing of Escherichia coli (E. coli), two important functions of activated macrophages. Vimentin knockout mice also show a lesser rate of mortality following intraperitoneal challenge with lethal doses of E. coli, as compared to wild-type mice. Further, treatment with anti-vimentin antibodies protects mice from intraperitoneal infection with lethal doses of E. coli. Our findings strongly suggest an important role for vimentin as part of the immune response to bacterial inflammation and may lead to the development of new therapeutic targets for the treatment of bacterial inflammation and sepsis.

We have also demonstrated that cellular activation and differentiation of macrophages cause the secretion of DEK, previously considered to be a strictly nuclear protein. The secretion of the nuclear DEK protein is stimulated by Interleukin-8 and inhibited by certain immunosuppressive agents like dexamethasone and cyclosporin A. DEK is secreted into the extracellular space of activated macrophages and synovial mononuclear cells via exosome-like vesicles that are thought to be capable of antigen presentation, as well as by another unknown pathway. Moreover, a high level of DEK protein is detected in synovial fluids from patients with juvenile arthritis. Additionally, cell migration assays indicate that recombinant DEK acts as a lymphocyte, neutrophil, and perhaps endothelial cell chemoattractant via the CXCR1/CXCR2 receptors, suggesting that DEK amplifies the local immune response in the joint space. In view of that above and recent reports of antibody to DEK being found in some children with juvenile idiopathic arthritis (JIA) and related diseases, studying the role of DEK in the pathogenesis of inflammation and autoimmune disease holds great promise for improving our knowledge of how these conditions begin, and how they might be treated more effectively.

Recent Publications:

Mor-Vaknin N., Punturieri A., Sitwala K., and Markovitz D.M. (2003). The Intermediate filament protein vimentin is secreted by activated macrophages. Nat Cell Biol. 5(1):59-63.

Sitwala K.V., Mor-Vaknin N., Markovitz D.M. (2003). Minireview: DEK and gene regulation, oncogenesis and AIDS. Anticancer Res. 23(3A):2155-8.

Xu B., deWaal R.M., Mor-Vaknin N., Hibbard C., Markovitz D.M., Kahn ML. (2004). The endothelial cell-specific antibody PAL-E identifies a secreted form of vimentin in the blood vasculature.
Mol Cell Biol. 24(20):9198-206.

Cleary J., Sitwala K.V., Khodadoust M.S., Kwok R.P., Mor-Vaknin, N., Cebart M., Cole P.A. and Markovitz D.M. (2005). P/CAF drives DEK into interchromatin granule clusters. J Biol Chem. 280: 371760-7.

Mor-Vaknin N., Punturieri A., Sitwala K., Faulkner N., Legendre M., Khodadoust M., Ferdinand K,. Ruth H.J., Koch A., Glass D., Petruzzelli L., Adams S.B., and Markovitz D.M. The DEK nuclear autoantigen is a secreted chemotactic factor. Mol Cell Biol. (2006) Dec;26(24):9484-96.

Bargagna-Mohan P., Hamza A., Kim Y.E., Khuan Abby Ho Y., Mor-Vaknin N., Wendschlag N., Liu J., Evans R.M., Markovitz D.M., Zhan C.G., Kim K.B., Mohan R. The tumor inhibitor and antiangiogenic agent Withaferin A targets the intermediate filament protein vimentin. Chem Biol. (2007) Jun;14(6):623-34.