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

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(beta-) isoform directly acting over inflammatory phagocytes...

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Detalles Bibliográficos
Autores: Serrano, Inmaculada, Luque, Ana, Mitjavila Villeró, Francesca, Blom, Anna M., Rodríguez de Córdoba, Santiago, Vega Fernández, Maria Cristina, Torras Ambròs, Joan, Aran Perramon, Josep M.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/186085
Acceso en línea:https://hdl.handle.net/2445/186085
Access Level:acceso abierto
Palabra clave:Immunoregulació
Lupus
Immunoregulation
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spelling The Hidden Side of Complement Regulator C4BP: Dissection and Evaluation of Its Immunomodulatory ActivitySerrano, InmaculadaLuque, AnaMitjavila Villeró, FrancescaBlom, Anna M.Rodríguez de Córdoba, SantiagoVega Fernández, Maria CristinaTorras Ambròs, JoanAran Perramon, Josep M.ImmunoregulacióLupusImmunoregulationLupusC4b-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(beta-) isoform directly acting over inflammatory phagocytes. Here we show that incorporation of the beta-chain to the C4BP alpha-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 alpha-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-alpha. 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(beta-) and lacking its complement regulatory activity, might represent a promising and novel alternative to treat autoimmune diseases.Frontiers Media2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/186085Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.3389/fimmu.2022.883743Frontiers in Immunology, 2022, vol. 13https://doi.org/10.3389/fimmu.2022.883743cc by (c) Serrano, Inmaculada et al, 2022http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1860852026-05-27T06:46:51Z
dc.title.none.fl_str_mv The Hidden Side of Complement Regulator C4BP: Dissection and Evaluation of Its Immunomodulatory Activity
title The Hidden Side of Complement Regulator C4BP: Dissection and Evaluation of Its Immunomodulatory Activity
spellingShingle The Hidden Side of Complement Regulator C4BP: Dissection and Evaluation of Its Immunomodulatory Activity
Serrano, Inmaculada
Immunoregulació
Lupus
Immunoregulation
Lupus
title_short The Hidden Side of Complement Regulator C4BP: Dissection and Evaluation of Its Immunomodulatory Activity
title_full The Hidden Side of Complement Regulator C4BP: Dissection and Evaluation of Its Immunomodulatory Activity
title_fullStr The Hidden Side of Complement Regulator C4BP: Dissection and Evaluation of Its Immunomodulatory Activity
title_full_unstemmed The Hidden Side of Complement Regulator C4BP: Dissection and Evaluation of Its Immunomodulatory Activity
title_sort The Hidden Side of Complement Regulator C4BP: Dissection and Evaluation of Its Immunomodulatory Activity
dc.creator.none.fl_str_mv Serrano, Inmaculada
Luque, Ana
Mitjavila Villeró, Francesca
Blom, Anna M.
Rodríguez de Córdoba, Santiago
Vega Fernández, Maria Cristina
Torras Ambròs, Joan
Aran Perramon, Josep M.
author Serrano, Inmaculada
author_facet Serrano, Inmaculada
Luque, Ana
Mitjavila Villeró, Francesca
Blom, Anna M.
Rodríguez de Córdoba, Santiago
Vega Fernández, Maria Cristina
Torras Ambròs, Joan
Aran Perramon, Josep M.
author_role author
author2 Luque, Ana
Mitjavila Villeró, Francesca
Blom, Anna M.
Rodríguez de Córdoba, Santiago
Vega Fernández, Maria Cristina
Torras Ambròs, Joan
Aran Perramon, Josep M.
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Immunoregulació
Lupus
Immunoregulation
Lupus
topic Immunoregulació
Lupus
Immunoregulation
Lupus
description 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(beta-) isoform directly acting over inflammatory phagocytes. Here we show that incorporation of the beta-chain to the C4BP alpha-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 alpha-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-alpha. 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(beta-) and lacking its complement regulatory activity, might represent a promising and novel alternative to treat autoimmune diseases.
publishDate 2022
dc.date.none.fl_str_mv 2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/186085
url https://hdl.handle.net/2445/186085
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.3389/fimmu.2022.883743
Frontiers in Immunology, 2022, vol. 13
https://doi.org/10.3389/fimmu.2022.883743
dc.rights.none.fl_str_mv cc by (c) Serrano, Inmaculada et al, 2022
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Serrano, Inmaculada et al, 2022
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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