C-Reactive Protein Impairs Dendritic Cell Development, Maturation, and Function: Implications for Peripheral Tolerance

Abstract

C-reactive protein (CRP) is the prototypical acute phase reactant, increasing in blood concentration rapidly and several-fold in response to inflammation. Recent evidence indicates that CRP has an important physiological role even at low, baseline levels, or in the absence of overt inflammation. For example, we have shown that human CRP inhibits the progression of experimental autoimmune encephalomyelitis (EAE) in CRP transgenic mice by shifting CD4+ T cells away from the TH1 and toward the TH2 subset. Notably, this action required the inhibitory Fcγ receptor IIB (FcγRIIB), but did not require high levels of human CRP. Herein, we sought to determine if CRP’s influence in EAE might be explained by CRP acting on dendritic cells (DC; antigen presenting cells known to express FcγRIIB). We found that CRP (50 µg/ml) reduced the yield of CD11c+ bone marrow-derived DCs (BMDCs) and CRP (≥5 μg/ml) prevented their full expression of major histocompatibility complex class II and the co-stimulatory molecules CD86 and CD40. CRP also decreased the ability of BMDCs to stimulate antigen-driven proliferation of T cells in vitro. Importantly, if the BMDCs were genetically deficient in mouse FcγRIIB then (i) the ability of CRP to alter BMDC surface phenotype and impair T cell proliferation was ablated and (ii) CD11c-driven expression of a human FCGR2B transgene rescued the CRP effect. Lastly, the protective influence of CRP in EAE was fully restored in mice with CD11c-driven human FcγRIIB expression. These findings add to the growing evidence that CRP has important biological effects even in the absence of an acute phase response, i.e., CRP acts as a tonic suppressor of the adaptive immune system. The ability of CRP to suppress development, maturation, and function of DCs implicates CRP in the maintenance of peripheral T cell tolerance.

C reactive protein impairs adaptive immunity in immune cells of patients with melanoma

“…The finding in this study that serum CRP levels are associated with overall survival in patients with stage IV melanoma treated with nivolumab or ipilimumab further support an immune suppressive role for CRP and possibly other APPs and suggest a novel mechanism for resistance to PD-1 blockade in melanoma that may be applicable to other cancers. CRP has been shown to alter DC maturation and function in murine models, 31 although it has not been previously shown to behave similarly with human DCs, and few investigations have explored the impact of high levels of CRP on human T cells.…”

C-Reactive Protein Stimulates Nicotinic Acetylcholine Receptors to Control ATP-Mediated Monocytic Inflammasome Activation

“…It remains to be investigated if the here described mechanism also contributes to the protection against experimental inflammation in animals overexpressing human CRP ( 25 – 28 ). Interestingly, CRP was recently shown to impair dendritic cell development, maturation and function ( 60 ). This anti-inflammatory mechanism involves the inhibitory Fcγ receptor IIB ( 60 ).…”

Thrombogenic and Inflammatory Reactions to Biomaterials in Medical Devices

“…Dendritic cells are fundamental players of both innate and adaptive immunity and could induce a tolerogenic effect on biomaterials by releasing interleukin-10 (Franz et al, 2011) following native CRP stimulation ( Figure 5). It has been recently proposed that native CRP down-regulates dendritic cell development and activation/maturation through Fc gamma receptor IIB (Fcγ RIIB), so it acts as a stopper on T cell mediated immunity, shifting the balance toward tolerance (Jimenez et al, 2018) (Figure 5). Inducing tolerogenic capabilities of biomaterials appears a promising strategy to down-regulate the host immune responses and resolve inflammation.…”