Abstract
Previously we established that human C-reactive protein (CRP) exacerbates mouse acute kidney injury and that the effect was associated with heightened renal accumulation of myeloid derived cells with suppressor functions (MDSC). Herein we provide direct evidence that CRP modulates the development and suppressive actions of MDSCs in vitro. We demonstrate that CRP dose-dependently increases the generation of MDSC from wild type mouse bone marrow progenitors and enhances MDSC production of intracellular reactive oxygen species (iROS). When added to co-cultures, CRP significantly enhanced the ability of MDSCs to suppress CD3/CD28-stimulated T cell proliferation. Experiments using MDSCs from FcγRIIB deficient mice (FcγRIIB−/−) showed that CRP's ability to expand MDSCs and trigger their increased production of iROS was FcγRIIB-independent, whereas its ability to enhance the MDSC T cell suppressive action was FcγRIIB-dependent. Importantly, CRP also enabled freshly isolated primary human neutrophils to suppress proliferation of autologous T cells. These findings suggest that CRP might be an endogenous regulator of MDSC numbers and actions in vivo.
Highlights
Human C-reactive protein (CRP) is the prototypical acute phase reactant; CRP serum levels can rapidly increase from typically ≤3 μg/ml at baseline to upwards of 500 μg/ml in response to proinflammatory cytokines produced during inflammation (e.g., IL-6, IL-1β, and TNFα) [1, 2]
After 4 days in culture the majority of cells recovered either retained an immature myelocyte mononuclear appearance or had ring-shaped nuclei, while fewer had a polymorphonuclear appearance typical of mature granulocytes (Figure 1A); this heterogeneity is consistent with the reported range of nuclear morphologies characteristic of myeloid derived cells with suppressor functions (MDSC) found in vivo in both mice and humans [28]
To determine the impact of CRP on the growth of mouse bone marrow progenitors, human CRP was added to cultures and their cell cycling was assessed by flow cytometry after BrdU/7aminoactinomycin D (7-AAD) incorporation
Summary
Human C-reactive protein (CRP) is the prototypical acute phase reactant; CRP serum levels can rapidly increase from typically ≤3 μg/ml at baseline to upwards of 500 μg/ml in response to proinflammatory cytokines produced during inflammation (e.g., IL-6, IL-1β, and TNFα) [1, 2]. Its wide-ranging blood levels and sensitivity to inflammation make human CRP a useful clinical biomarker of diseases such as cardiovascular, autoimmune, and Alzheimer’s disease [9, 10]. CRP levels are often monitored in patients with acute kidney injury (AKI) wherein they correlate with increased AKI risk, severity, and clinical outcomes [11,12,13]. Our group recently established that expression of human CRP (by CRP transgenic mice; CRPtg) exacerbated renal ischemia reperfusion injury, an experimental model of AKI [14]. The detrimental action of CRP was associated with an increased renal accumulation of myeloid cells with a suppressor phenotype (hereafter, MDSC)
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