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The Hidden Side of Complement Regulator C4BP : Dissection and Evaluation of Its Immunomodulatory Activity

Serrano, Inmaculada ; Luque, Ana ; Mitjavila, Francesca ; Blom, Anna M. LU orcid ; Rodríguez de Córdoba, Santiago ; Vega, M. Cristina ; Torras, Joan and Aran, Josep M. (2022) In Frontiers in Immunology 13.
Abstract

C4b-binding protein (C4BP) is a well-known regulator of the complement system that holds additional and important activities unrelated to complement inhibition. Recently, we have described a novel immunomodulatory activity in the minor C4BP(β-) isoform directly acting over inflammatory phagocytes. Here we show that incorporation of the β-chain to the C4BP α-chain oligomer interferes with this immunomodulatory activity of C4BP. Moreover, an oligomeric form including only the complement control protein 6 (CCP6) domain of the C4BP α-chain (PRP6-HO7) is sufficient to “reprogram” monocyte-derived DCs (Mo-DCs) from a pro-inflammatory and immunogenic phenotype to an anti-inflammatory and tolerogenic state. PRP6-HO7 lacks complement regulatory... (More)

C4b-binding protein (C4BP) is a well-known regulator of the complement system that holds additional and important activities unrelated to complement inhibition. Recently, we have described a novel immunomodulatory activity in the minor C4BP(β-) isoform directly acting over inflammatory phagocytes. Here we show that incorporation of the β-chain to the C4BP α-chain oligomer interferes with this immunomodulatory activity of C4BP. Moreover, an oligomeric form including only the complement control protein 6 (CCP6) domain of the C4BP α-chain (PRP6-HO7) is sufficient to “reprogram” monocyte-derived DCs (Mo-DCs) from a pro-inflammatory and immunogenic phenotype to an anti-inflammatory and tolerogenic state. PRP6-HO7 lacks complement regulatory activity but retains full immunomodulatory activity over inflammatory Mo-DCs induced by TLRs, characterized by downregulation of relevant surface markers such as CD83, HLA-DR, co-stimulatory molecules such as CD86, CD80 and CD40, and pro-inflammatory cytokines such as IL-12 and TNF-α. Furthermore, PRP6-HO7-treated Mo-DCs shows increased endocytosis, significantly reduced CCR7 expression and CCL21-mediated chemotaxis, and prevents T cell alloproliferation. Finally, PRP6-HO7 shows also full immunomodulatory activity over Mo-DCs isolated from lupus nephritis patients with active disease, even without further pro-inflammatory stimulation. Therefore PRP6-HO7, retaining the immunomodulatory activity of C4BP(β-) and lacking its complement regulatory activity, might represent a promising and novel alternative to treat autoimmune diseases.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
C4BP(β-), dendritic cells, immunomodulation, inflammation, lupus nephritis, PRP6-HO7
in
Frontiers in Immunology
volume
13
article number
883743
publisher
Frontiers Media S. A.
external identifiers
  • pmid:35547734
  • scopus:85130636560
ISSN
1664-3224
DOI
10.3389/fimmu.2022.883743
language
English
LU publication?
yes
additional info
Publisher Copyright: Copyright © 2022 Serrano, Luque, Mitjavila, Blom, Rodríguez de Córdoba, Vega, Torras and Aran.
id
daa49fd6-b2c7-4a45-af27-870ce7227d84
date added to LUP
2022-08-19 12:56:15
date last changed
2024-04-18 05:08:48
@article{daa49fd6-b2c7-4a45-af27-870ce7227d84,
  abstract     = {{<p>C4b-binding protein (C4BP) is a well-known regulator of the complement system that holds additional and important activities unrelated to complement inhibition. Recently, we have described a novel immunomodulatory activity in the minor C4BP(β-) isoform directly acting over inflammatory phagocytes. Here we show that incorporation of the β-chain to the C4BP α-chain oligomer interferes with this immunomodulatory activity of C4BP. Moreover, an oligomeric form including only the complement control protein 6 (CCP6) domain of the C4BP α-chain (PRP6-HO7) is sufficient to “reprogram” monocyte-derived DCs (Mo-DCs) from a pro-inflammatory and immunogenic phenotype to an anti-inflammatory and tolerogenic state. PRP6-HO7 lacks complement regulatory activity but retains full immunomodulatory activity over inflammatory Mo-DCs induced by TLRs, characterized by downregulation of relevant surface markers such as CD83, HLA-DR, co-stimulatory molecules such as CD86, CD80 and CD40, and pro-inflammatory cytokines such as IL-12 and TNF-α. Furthermore, PRP6-HO7-treated Mo-DCs shows increased endocytosis, significantly reduced CCR7 expression and CCL21-mediated chemotaxis, and prevents T cell alloproliferation. Finally, PRP6-HO7 shows also full immunomodulatory activity over Mo-DCs isolated from lupus nephritis patients with active disease, even without further pro-inflammatory stimulation. Therefore PRP6-HO7, retaining the immunomodulatory activity of C4BP(β-) and lacking its complement regulatory activity, might represent a promising and novel alternative to treat autoimmune diseases.</p>}},
  author       = {{Serrano, Inmaculada and Luque, Ana and Mitjavila, Francesca and Blom, Anna M. and Rodríguez de Córdoba, Santiago and Vega, M. Cristina and Torras, Joan and Aran, Josep M.}},
  issn         = {{1664-3224}},
  keywords     = {{C4BP(β-); dendritic cells; immunomodulation; inflammation; lupus nephritis; PRP6-HO7}},
  language     = {{eng}},
  month        = {{04}},
  publisher    = {{Frontiers Media S. A.}},
  series       = {{Frontiers in Immunology}},
  title        = {{The Hidden Side of Complement Regulator C4BP : Dissection and Evaluation of Its Immunomodulatory Activity}},
  url          = {{http://dx.doi.org/10.3389/fimmu.2022.883743}},
  doi          = {{10.3389/fimmu.2022.883743}},
  volume       = {{13}},
  year         = {{2022}},
}