Extracellular vimentin modulates human dendritic cell activation

Abstract

Vimentin is an intermediate filament protein traditionally considered to be an intracellular protein with a structural role. However, recent evidence suggests that vimentin can also be found outside the cell in disease conditions such as cancer, traumatic tissue injury, and inflammation. Extracellular vimentin was previously found to stimulate innate immunity by increasing monocyte and macrophage ability to kill bacteria. However, vimentin has also been previously found to decrease neutrophil infiltration into inflamed tissue. How extracellular vimentin affects the initiation of adaptive immune responses is unknown. Initiation of adaptive immunity involves priming of naïve T cells by antigen-presenting cells, the most effective of which are dendritic cells (DCs). In this study, we demonstrate how extracellular vimentin modulates lipopolysaccharide (LPS) – induced activation of human DCs. Using cytometric bead arrays, we show that extracellular vimentin decreases LPS-activated DC secretion of pro-inflammatory cytokines IL-6 and IL-12 while increasing secretion of the anti-inflammatory cytokine IL-10. Using flow cytometry, we show that extracellular vimentin does not significantly affect LPS-induced DC surface expression of MHC I (HLA-ABC) or MHC II (HLA-DR) presentation molecules, costimulatory factors (CD80, CD86), or the DC maturation marker (CD83). Further, LPS-stimulated DCs co-cultured with allogeneic naïve CD4 + T cells (Th0) induced less secretion of the pro-inflammatory Th1 effector cytokine IFN-γ in the presence of vimentin than in the presence of LPS alone. This result suggests that vimentin reduces Th1 differentiation. Taken together, our data suggest that extracellular vimentin may inhibit pro-inflammatory adaptive immune responses, by blocking DC secretion of pro-inflammatory cytokines. Thus, extracellular vimentin may play an important role in cancer or trauma-complications by inducing suppression of the adaptive immune response. In a positive sense, the presence of extracellular vimentin may prevent tissue-damage from contributing to the development of autoimmunity. Consequently, extracellular vimentin may become a novel drug target for treatment of a variety of pro- and anti-inflammatory disease conditions.