The complement inhibitor factor H generates an anti-inflammatory and tolerogenic state in monocyte-derived dendritic cells

Research output: Contribution to journalArticle

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.

Details

Authors
  • Rut Olivar
  • Ana Luque
  • Sonia Cárdenas-Brito
  • Francesc E. Borras
  • Mar Naranjo-Gómez
  • Anna M. Blom
  • Santiago Rodriguez De Córdoba
  • Peter F. Zipfel
  • Josep M. Aran
Organisations
External organisations
  • Bellvitge Biomedical Research Institute
  • Institute for Health Science Research Germans Trias i Pujol (IGTP)
  • Biological Research Center (CIB), Madrid
  • Leibniz Institute for Natural Product Research and Infection Biology
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Immunology in the medical area
Original languageEnglish
Pages (from-to)4274-4290
Number of pages17
JournalJournal of Immunology
Volume196
Issue number10
Publication statusPublished - 2016 May 15
Publication categoryResearch
Peer-reviewedYes