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...
| Autores: | , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:2445/186085 |
| Acceso en línea: | https://hdl.handle.net/2445/186085 |
| Access Level: | acceso abierto |
| Palabra clave: | Immunoregulació Lupus Immunoregulation |
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oai:recercat.cat:2445/186085 |
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ES |
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España |
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The Hidden Side of Complement Regulator C4BP: Dissection and Evaluation of Its Immunomodulatory Activity 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. Immunoregulació Lupus Immunoregulation 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. Frontiers Media https://hdl.handle.net/2445/186085 |
| 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 |
| 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 |
| 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 |
| topic |
Immunoregulació Lupus Immunoregulation |
| topic_facet |
Immunoregulació Lupus Immunoregulation |
| 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 |
| format |
article |
| status_str |
publishedVersion |
| url |
https://hdl.handle.net/2445/186085 |
| eu_rights_str_mv |
openAccess |
| publisher |
Frontiers Media |
| institution |
Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| collection |
Recercat. Dipósit de la Recerca de Catalunya |
| reponame_str |
Recercat. Dipósit de la Recerca de Catalunya |
| instname_str |
Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| _version_ |
1878438703343337472 |
| publishDateSort |
2022 |
| author_browse |
Aran Perramon, Josep M. Blom, Anna M. Luque, Ana Mitjavila Villeró, Francesca Rodríguez de Córdoba, Santiago Serrano, Inmaculada Torras Ambròs, Joan Vega Fernández, Maria Cristina |
| publisherStr |
Frontiers Media |
| score |
6.924472 |