C-reactive protein impairs dendritic cell development, maturation, and function: Implications for peripheral tolerance

Rachel V. Jimenez, Tyler T. Wright, Nicholas R. Jones, Jianming Wu, Andrew W. Gibson, Alexander J. Szalai

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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.

Original languageEnglish (US)
Article number372
JournalFrontiers in immunology
Volume9
Issue numberMAR
DOIs
StatePublished - Mar 5 2018

Bibliographical note

Funding Information:
The authors thank the members of the UAB Comprehensive Flow Cytometry Core facility [supported by National Institutes of Health (NIH) Grants P30 AR048311 and P30 AI27667] and the UAB Transgenic & Genetically Engineered Model Systems Core facility (supported by awards NIH P30 CA13148, P30 AR048311, P30 DK074038, P30 DK05336, and P60 DK079626). This research was funded in part by National Institutes of Health grants 1F31NS081903 (TW), 1R01DK099092 (AS), and 1F31DK112646-01 (RJ).

Keywords

  • Acute phase response
  • Aging
  • Autoimmunity
  • Inflammaging
  • Inflammation
  • Transgenic

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