The Hidden Side of Complement Regulator C4BP : Dissection and Evaluation of Its Immunomodulatory Activity
(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.
(Less)
- author
- Serrano, Inmaculada ; Luque, Ana ; Mitjavila, Francesca ; Blom, Anna M. LU ; Rodríguez de Córdoba, Santiago ; Vega, M. Cristina ; Torras, Joan and Aran, Josep M.
- organization
- publishing date
- 2022-04-25
- 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}}, }