Hepatic but Not CNS-Expressed Human C-Reactive Protein Inhibits Experimental Autoimmune Encephalomyelitis in Transgenic Mice

Wright, Tyler; Jimenez, Rachel V.; Morgan, Todd E.; Bali, Namrata; Hou, Xiaogang; McCrory, Mark A.; Finch, Caleb E.; Szalai, Alexander J.

doi:10.1155/2015/640171

Cited by 6 publications

(9 citation statements)

References 28 publications

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“…We had previously shown that CRPtg undergoing EAE have delayed onset and reduced severity of disease compared to WT and that this beneficial effect of CRP is FcγRIIB-dependent ( 5 , 6 , 20 , 25 ), and herein we provide new evidence that this FcγRIIB-dependency extends to BMDCs in vitro . Moreover, although not all the observed effects of human CRP on BMDCs were supported by human FcγRIIB, CD11c-specific expression of human FcγRIIB was sufficient to fully reconstitute human CRP’s beneficial actions in EAE (Figure 7 ; Table 1 ).…”

Section: Resultssupporting

confidence: 60%

“…Previously, we showed that human CRP protects CRPtg mice from EAE triggered either directly by immunization with MOG or indirectly by the transfer of MOG-specific T cells ( 5 , 20 , 25 ) and that this protection was FcγRIIB-dependent manner ( 6 ). Although human CRP can have direct effects on T cells ( 25 ), the initial evidence of CRP inhibiting EAE suggested that CRP most likely conferred protection by acting on an intermediary APC.…”

Section: Discussionmentioning

confidence: 98%

“…Experimental autoimmune encephalomyelitis was induced as we described previously ( 5 , 6 , 20 ). Briefly, 10–12-week-old mice were immunized subcutaneously with 150 µg MOG 35–55 emulsified in Freund’s complete adjuvant plus 400 µg heat-killed Mycobacterium tuberculosis (Difco, Detroit, MI, USA).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2018

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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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Section: Resultssupporting

confidence: 60%

Section: Discussionmentioning

confidence: 98%

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

et al. 2018

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“…In the past decade, AE cases have been increasingly recognized due to the discovery of neuron-specific autoantibodies in the blood and/or cerebrospinal fluid (CSF) (Dubey et al, 2016). The pathogenic role of antibodies has been demonstrated by the passive transfer of autoantibodies to animal models, which recapitulated the effects of autoantibodies and the clinical manifestations of AE (Planaguma et al, 2015; Wright et al, 2015). However, the mechanisms through which these autoantibodies are generated and enter the central nervous system (CNS) remain elusive.…”

Section: Introductionmentioning

confidence: 96%

S100A6 Promotes B Lymphocyte Penetration Through the Blood–Brain Barrier in Autoimmune Encephalitis

Tsai

Lin

et al. 2019

Front. Genet.

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Autoimmune encephalitis (AE) is a severe neurological disease. The brain of the AE patient is attacked by a dysregulated immune system, which is caused by the excessive production of autoantibodies against neuronal receptors and synaptic proteins. AE is also characterized by the uncontrolled B lymphocyte infiltration through the blood–brain barrier (BBB) layer, and the investigation of the underlying mechanism involved in this infiltration may facilitate the discovery of novel therapies for AE. However, few AE-related studies have focused on this issue. In this study, we aimed to identify the factors involved in B lymphocyte infiltration in AE. For this purpose, we first enrolled four healthy control and five AE subjects, collecting their serum and/or total white blood cell samples. The white blood cell samples were further used for collecting RNA and DNA. Then, we simulated the in vivo B lymphocyte infiltration with an in vitro leukocyte transendothelial migration model. It turned out that AE serum treatment significantly and specifically promoted B cells to penetrate the BBB endothelial layer without affecting neutrophils. Next, through genome-wide DNA methylation assays on bisulfite-conversion DNA samples, we identified S100A6 and S100A11 as potential hypo-methylated disease genes in the AE samples. Further qPCR assays demonstrated their upregulation in AE samples, reflecting the negative correlations between gene expression and DNA methylation. Finally, recombinant S100A6 protein treatment significantly increased B lymphocyte infiltration through the BBB endothelial layer, which partially recapitulated the effect of AE serum. In summary, by using an in vitro leukocyte transendothelial migration model, we confirmed that S100A6 promoted B lymphocyte to penetrate the BBB endothelial layer, which is similar to the in vivo clinical manifestations of AE. Therefore, further studies on how the S100A6 protein facilitates B lymphocyte infiltration and on whether other factors in serum also contribute to this phenomenon are likely to improve our understanding of AE and hopefully to reveal novel therapeutic targets for this emerging treatable neurological disorder.

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“…Several reports also indicate that CRP can promote the production of the anti-inflammatory cytokine IL-10, suggesting that elevated CRP levels may by a means to downregulate inflammation [ 17 , 18 , 53 , 54 ]. The effect of CRP may be further complicated by the relative levels of CRP in the circulation compared to the tissue or inflammatory site, as transgenic mice expressing CRP in lesions have differential responses to mice with high levels of systemic CRP [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

Monocyte differentiation and macrophage priming are regulated differentially by pentraxins and their ligands

et al. 2017

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BackgroundCirculating bone marrow-derived monocytes can leave the blood, enter a tissue, and differentiate into M1 inflammatory, M2a remodeling/fibrotic, or M2c/Mreg resolving/immune-regulatory macrophages. Macrophages can also convert from one of the above types to another. Pentraxins are secreted proteins that bind to, and promote efficient clearance of, microbial pathogens and cellular debris during infection, inflammation, and tissue damage. The pentraxins C-reactive protein (CRP), serum amyloid P (SAP), and pentraxin-3 (PTX3) can also bind a variety of endogenous ligands. As monocytes and macrophages are exposed to differing concentrations of pentraxins and their ligands during infection, inflammation, and tissue damage, we assessed what effect pentraxins and their ligands have on these cells.ResultsWe found that many polarization markers do not discriminate between the effects of pentraxins and their ligands on macrophages. However, pentraxins, their ligands, and cytokines differentially regulate the expression of the hemoglobin-haptoglobin complex receptor CD163, the sialic acid-binding lectin CD169, and the macrophage mannose receptor CD206. CRP, a pentraxin generally thought of as being pro-inflammatory, increases the extracellular accumulation of the anti-inflammatory cytokine IL-10, and this effect is attenuated by GM-CSF, mannose-binding lectin, and factor H.ConclusionsThese results suggest that the presence of pentraxins and their ligands regulate macrophage differentiation in the blood and tissues, and that CRP may be a potent inducer of the anti-inflammatory cytokine IL-10.Electronic supplementary materialThe online version of this article (doi:10.1186/s12865-017-0214-z) contains supplementary material, which is available to authorized users.

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Hepatic but Not CNS-Expressed Human C-Reactive Protein Inhibits Experimental Autoimmune Encephalomyelitis in Transgenic Mice

Cited by 6 publications

References 28 publications

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

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

S100A6 Promotes B Lymphocyte Penetration Through the Blood–Brain Barrier in Autoimmune Encephalitis

Monocyte differentiation and macrophage priming are regulated differentially by pentraxins and their ligands

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