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fimmu-13-883743.pdf (5.82 MB)

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2022-04-25

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cc by (c) Serrano, Inmaculada et al, 2022
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/186085

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

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https://doi.org/10.3389/fimmu.2022.883743

Resum

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.

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Immunoregulació, Lupus

Matèries (anglès)

Immunoregulation, Lupus

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Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

Citació

SERRANO, Inmaculada, et al. The Hidden Side of Complement Regulator C4BP: Dissection and Evaluation of Its Immunomodulatory Activity. Frontiers in Immunology. 2022. Vol. 13. ISSN 1664-3224. [consulted: 5 of June of 2026]. Available at: https://hdl.handle.net/2445/186085

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