C‐reactive protein impairs human CD14⁺ monocyte‐derived dendritic cell differentiation, maturation and function

Abstract

C-reactive protein (CRP) is an acute phase reactant protein considered to be the prototypic marker for inflammation and its associated diseases. However, little is known about how CRP affects the immune system. In this study, we investigated the effect of CRP on dendritic cell (DC) differentiation, activation and biological functions. CD14 + monocytes were purified from PBMC and differentiated into DC in vitro. CRP (10 lg/ mL) substantially down-regulated expression of DC-SIGN (CD209) and the costimulatory molecules CD40 and CD86 during DC differentiation. This inhibitory effect was more pronounced when CRP was added at the early stage (0-2 days) of DC differentiation. The inhibitory effect of CRP could be specifically blocked by an anti-CD32 Ab. In addition, CRP dramatically down-regulated expression of the antigenuptake molecules CD205 and CD206, resulting in reduced DC endocytosis. Furthermore, CRP down-regulated expression of the costimulatory molecules CD40, CD80 and CD86 as well as the DC maturation marker CD83 after lipopolysaccharideinduced DC maturation. CRP-treated DC also showed an inhibitory effect on allogeneic T cell proliferation in a mixed leukocyte reaction. CRP treatment of activated DC preferentially decreased production of the proinflammatory and inflammatory cytokines IL-6, IL-8, IL-12, TNF-a, MIP-1a, MIP-1b and MCP-1. This work reveals a new role for CRP in modulating the immune system by inhibiting DC differentiation, maturation and functions mainly through FccRIIa/CD32.

C-reactive protein increases plasminogen activator inhibitor-1 expression in human endothelial cells

“…In our previous studies, we have demonstrated that CRP decreased the expression of thrombomodulin, endothelial protein C receptor, VEGF receptors and neuropilins in human endothelial cells [26,27]. In addition, we reported that CRP was able to regulate human dendritic cell differentiation in vitro [28]. Our current findings along with our previous investigations and other reports could provide more comprehensive information towards understanding the role and mechanisms of CRP for cardiovascular disease and other systems.…”

“…Recent studies in human subjects demonstrated that infusion of recombinant human CRP caused endothelial dysfunction and activation of several inflammation cytokines as well as coagulation including PAI-1 upregulation [28,38]. These studies are of great significance because findings convincingly showed the biomediator roles of CRP in humans.…”

Regulated conformation changes in C-reactive protein orchestrate its role in atherogenesis

“…Knock-in of human CRP in rabbits, on the other hand, appeared to reduce the lesion formation, albeit with no statistical significance [35]. Even worse is that in vitro studies frequently generate conflicting results [36][37][38][39][40][41][42][43][44][45] and some of the reported activities of CRP have been ascribed to impurities such as azide or endotoxin [39,46,47]. The acute-phase reactant nature of CRP adds an additional layer of complexity: how does a protein with two to three orders of dynamic fluctuation in its plasma levels function as a fine modulator of sophisticated cellular or physiological systems [1]?…”

“…Moreover, disruption of lipid rafts by MβCD or nystatin eliminated the stimulation effects of Cysmutated mCRP on EC and in rabbit vessels. Accordingly, we identified a cholesterol binding motif (CBM; a.a. [35][36][37][38][39][40][41][42][43][44][45][46][47] containing Cys36 in the sequence of human CRP which has been conserved throughout evolution. Indeed, reduction or mutating cysteines promoted the interactions of Cysmutated or reduced mCRP with both model and cell membranes.…”

The Acute-Phase Reactant C-Reactive Protein Binds to Phosphorylcholine-ExpressingNeisseria meningitidisand Increases Uptake by Human Phagocytes

“…C-reactive protein (CRP) has long been recognized as a key player in the innate response to pathogenic infection and has been suggested to play a possible role in linking innate and acquired immune responses (41). This ancient member of the pentraxin family was discovered in 1930 as a serum protein that precipitated with the cell wall C polysaccharide of Streptococcus pneumoniae (34).…”