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

Autor:	Serrano I; Immune-inflammatory Processes and Gene Therapeutics Group, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain., Luque A; Immune-inflammatory Processes and Gene Therapeutics Group, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain., Mitjavila F; Internal Medicine Service, Bellvitge University Hospital, University of Barcelona and Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain., Blom AM; Department of Translational Medicine, Section of Medical Protein Chemistry, Lund University, Malmö, Sweden., Rodríguez de Córdoba S; Molecular Pathology/Genetics of Complement Group, Centro de Investigaciones Biológicas Margarita Salas (CSIC) and Ciber de Enfermedades Raras (CIBERER), Madrid, Spain., Vega MC; Structural Biology of Host-Pathogen Interactions Group, Centro de Investigaciones Biológicas Margarita Salas (CSIC), Madrid, Spain., Torras J; Nephrology Department, Bellvitge University Hospital, Experimental Nephrology Lab., University of Barcelona and Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain., Aran JM; Immune-inflammatory Processes and Gene Therapeutics Group, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2022 Apr 25; Vol. 13, pp. 883743. Date of Electronic Publication: 2022 Apr 25 (Print Publication: 2022).
DOI:	10.3389/fimmu.2022.883743
Abstrakt:	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. Competing Interests: IS, AL and JA are co-inventors on pending or issued patents involving compounds and methods for immunomodulation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Serrano, Luque, Mitjavila, Blom, Rodríguez de Córdoba, Vega, Torras and Aran.)
Databáze:	MEDLINE
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