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 journalArticle

3 Citations (Scopus)

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

Fingerprint

Peripheral Tolerance
C-Reactive Protein
Dendritic Cells
Fc Receptors
Autoimmune Experimental Encephalomyelitis
Bone Marrow
T-Lymphocytes
Inflammation
Acute-Phase Reaction
Acute-Phase Proteins

Keywords

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

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

Cite this

C-reactive protein impairs dendritic cell development, maturation, and function : Implications for peripheral tolerance. / Jimenez, Rachel V.; Wright, Tyler T.; Jones, Nicholas R.; Wu, Jianming; Gibson, Andrew W.; Szalai, Alexander J.

In: Frontiers in immunology, Vol. 9, No. MAR, 372, 05.03.2018.

Research output: Contribution to journalArticle

Jimenez, Rachel V. ; Wright, Tyler T. ; Jones, Nicholas R. ; Wu, Jianming ; Gibson, Andrew W. ; Szalai, Alexander J. / C-reactive protein impairs dendritic cell development, maturation, and function : Implications for peripheral tolerance. In: Frontiers in immunology. 2018 ; Vol. 9, No. MAR.
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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.",
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