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- Olivar, Rut, et al.
(författare)
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The alpha(7)beta(0) Isoform of the Complement Regulator C4b-Binding Protein Induces a Semimature, Anti-Inflammatory State in Dendritic Cells
- 2013
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 190:6, s. 2857-2872
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Tidskriftsartikel (refereegranskat)abstract
- The classical pathway complement regulator C4b-binding protein (C4BP) is composed of two polypeptides (alpha- and beta-chains), which form three plasma oligomers with different subunit compositions (alpha(7)beta(1), alpha(7)beta(0), and alpha(6)beta(1)). We show in this article that the C4BP alpha(7)beta(0) isoform (hereafter called C4BP[beta(-)] [C4BP lacking the beta-chain]), overexpressed under acute-phase conditions, induces a semimature, tolerogenic state on human monocyte-derived dendritic cells (DCs) activated by a proinflammatory stimulus. C4BP isoforms containing beta-chain (alpha(7)beta(1) and alpha(6)beta(1); C4BP[beta(+)]) neither interfered with the normal maturation of DCs nor competed with C4BP(beta(-)) activity on these cells. Immature DCs (iDCs) treated with C4BP(beta(-)) retained high endocytic activity, but, upon LPS treatment, they did not upregulate surface expression of CD83, CD80, and CD86. Transcriptional profiling of these semimature DCs revealed that treatment with C4BP(beta(-)) prevented the induction of IDO and BIC-1, whereas TGF-beta 1 expression was maintained to the level of iDCs. C4BP(beta(-))-treated DCs were also unable to release proinflammatory Th1 cytokines (IL-12, TNF-alpha, IFN-gamma, IL-6, IL-8) and, conversely, increased IL-10 secretion. They prevented surface CCR7 overexpression and, accordingly, displayed reduced chemotaxis, being morphologically indistinguishable from iDCs. Moreover, C4BP(beta(-))-treated DCs failed to enhance allogeneic T cell proliferation, impairing IFN-gamma production in these cells and, conversely, promoting CD4(+)CD127(low/neg) CD25(high)Foxp3(+) T cells. Deletion mutant analysis revealed that the complement control protein-6 domain of the alpha-chain is necessary for the tolerogenic activity of C4BP(beta(-)). Our data demonstrate a novel anti-inflammatory and immunomodulatory function of the complement regulator C4BP, suggesting a relevant role of the acute-phase C4BP(beta(-)) isoform in a number of pathophysiological conditions and potential applications in autoimmunity and transplantation. The Journal of Immunology, 2013, 190: 2857-2872.
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| 2. |
- Olivar, Rut, et al.
(författare)
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The complement inhibitor factor H generates an anti-inflammatory and tolerogenic state in monocyte-derived dendritic cells
- 2016
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 196:10, s. 4274-4290
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Tidskriftsartikel (refereegranskat)abstract
- The activation of the complement system is a key initiating step in the protective innate immune-inflammatory response against injury, although it may also cause harm if left unchecked. The structurally related soluble complement inhibitors C4b-binding protein (C4BP) and factor H (FH) exert a tight regulation of the classical/lectin and alternative pathways of complement activation, respectively, attenuating the activity of the C3/C5 convertases and, consequently, avoiding serious damage to host tissues. We recently reported that the acute-phase C4BP isoform C4BP lacking the β-chain plays a pivotal role in the modulation of the adaptive immune responses. In this study, we demonstrate that FH acts in the early stages of monocyte to dendritic cell (DC) differentiation and is able to promote a distinctive tolerogenic and anti-inflammatory profile on monocyte-derived DCs (MoDCs) challenged by a proinflammatory stimulus. Accordingly, FH-treated and LPS-matured MoDCs are characterized by altered cytoarchitecture, resembling immature MoDCs, lower expression of the maturation marker CD83 and the costimulatory molecules CD40, CD80, and CD86, decreased production of key proinflammatory Th1-cytokines (IL-12, TNF-α, IFN-γ, IL-6, and IL-8), and preferential production of immunomodulatory mediators (IL-10 and TGF-β). Moreover, FH-treated MoDCs show low Ag uptake and, when challenged with LPS, display reduced CCR7 expression and chemotactic migration, impaired CD4+ T cell alloproliferation, inhibition of IFN-γ secretion by the allostimulated T cells, and, conversely, induction of CD4+CD127low/negativeCD25highFoxp3+ regulatory T cells. Thus, this novel noncanonical role of FH as an immunological brake able to directly affect the function of MoDCs in an inflammatory environment may exhibit therapeutic potential in hypersensitivity, transplantation, and autoimmunity.
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