Original Research ARTICLE
C-reactive protein impairs dendritic cell activation: implications for peripheral tolerance.
- 1Department of Medicine, University of Alabama at Birmingham, United States
- 2Drug Development, Southern Research Institute, United States
- 3Department of Veterinary and Biomedical Sciences, University of Minnesota, United States
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 towards 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 (BMDC) 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.
Keywords: acute phase response, Aging, Autoimmunity, Inflammaging, Inflammation, transgenic
Received: 23 Oct 2017;
Accepted: 09 Feb 2018.
Edited by:Blanca Molins, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Spain
Reviewed by:Michael T. Lotze, University of Pittsburgh Cancer Institute, United States
Cees Van Kooten, Leiden University, Netherlands
Copyright: © 2018 Jimenez, Wright, Jones, Wu, Gibson and Szalai. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Mrs. Rachel V. Jimenez, University of Alabama at Birmingham, Department of Medicine, 1825 University Boulevard, Shelby Biomedical Research Building, Birmingham, 35924, Alabama, United States, email@example.com
Dr. Alexander J. Szalai, University of Alabama at Birmingham, Department of Medicine, 1825 University Boulevard, Shelby Biomedical Research Building, Birmingham, 35924, Alabama, United States, firstname.lastname@example.org