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

• Published in: Frontiers in immunology 2022-04, Vol.13, p.883743-883743
• Main Authors: Serrano, Inmaculada, Luque, Ana, Mitjavila, Francesca, Blom, Anna M, Rodríguez de Córdoba, Santiago, Vega, M Cristina, Torras, Joan, Aran, Josep M
• Format: Article
• Language: English
• Subjects: Basic Medicine; C4BP(β-); Complement C4b-Binding Protein - metabolism; Cytokines; dendritic cells; Female; Humans; Immunologi inom det medicinska området; Immunology; Immunology in the medical area; Immunomodulation; inflammation; Lupus Nephritis; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Monocytes - metabolism; PRP6-HO7
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2022.883743

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.