C-Reactive Protein Binds to FcγRII and Impairs the Differentiation and Function of Dendritic Cells.

Human C-reactive protein (CRP) is an acute-phase protein, and elevated levels of CRP are present in patients with infections, inflammatory diseases, necrosis such as myocardial infarction, or malignancies including multiple myeloma (MM), lymphoma, and carcinoma. CRP has many biological functions and is involved in host defense, regulation of inflammation, and modulation of autoimmune diseases. Although our current understanding of CRP interaction with complement and Fcγ receptors (FcγR) has elucidated a regulatory role of CRP in these disease situations, it is not clear whether CRP affects the function of immune cells such as dendritic cells (DCs). In this study, we investigated the effect of CRP on DC differentiation, maturation, and function. CD14⁺ monocytes isolated from human peripheral blood mononuclear cells were cultured in RPMI-1640 medium supplemented with GM-CSF and IL-4 for 5 days to generate immature DCs (imDCs), and were further treated with IL-1β and TNF-α for 2 additional days to produce mature DCs (mDCs). CRP (5–100 μg/mL) was added to the cultures during DC differentiation (on days 0 and 3) or maturation (on day 5). The presence of CRP in cultures reduced imDC cell yields in a dose-dependent manner. Significantly lower cell yields were detected in cultures with 5 to 10 μg/mL CRP. Compared with untreated controls, CRP treatment (10 μg/mL) led to inhibited surface expression of DC-related molecules HLA-ABC, CD1a, CD40, and CD54; increased secretion of IL-6, IL-8, and IL-10; reduced production of TGF-β by imDCs; and decreased secretion of IL-12 by mDCs. Furthermore, the function of CRP-treated DCs was also impaired, evident by the markedly decreased ability of imDCs to phagocytose apoptotic cells and to uptake and present soluble antigen to antigen-specific T cells. Compared with untreated controls, CRP-treated mDCs had reduced capacity at activating allospecific T cells, which consequently secreted significantly lower amounts of IFN-γ, IL-2, and TNF-α compared with T cells activated by normal mDCs. Western blot analysis showed that CRP treatment led to inhibited phosphorylation of ERK and p38 MAPKs, and inhibited NFκB activity in the differentiating cells. Monocytes and DCs all express FcγRI (CD64), FcγRII (CD32), and FcγRIII (CD16), and the expression of FcγRII, but not FcγRI and FcγRIII, were upregulated on CRP-treated DCs. The detrimental effects of CRP on DCs were abrogated by blocking antibody against CRP and by antibody against FcγRII, but not against FcγRI or FcγRIII. These results indicate that CRP affected DC differentiation via binding to cell surface FcγRII. Taken together, this study demonstrates for the first time that CRP at high concentrations has detrimental effects on in vitro differentiation and function of DCs. Further studies will be needed to examine the clinical and biological relevance of this observation.