TY - JOUR
T1 - C-Reactive protein promotes inflammation through FcγR-Induced glycolytic reprogramming of human macrophages
AU - Newling, Melissa
AU - Sritharan, Lathees
AU - van der Ham, Alwin J.
AU - Hoepel, Willianne
AU - Fiechter, Renee H.
AU - de Boer, Leonie
AU - Zaat, Sebastian A. J.
AU - Bisoendial, Radjesh J.
AU - Baeten, Dominique L. P.
AU - Everts, Bart
AU - den Dunnen, Jeroen
PY - 2019
Y1 - 2019
N2 - C-reactive protein (CRP) is an acute-phase protein produced in high quantities by the liver in response to infection and during chronic inflammatory disorders. Although CRP is known to facilitate the clearance of cell debris and bacteria by phagocytic cells, the role of CRP in additional immunological functions is less clear. This study shows that complexed CRP (phosphocholine [PC]:CRP) (formed by binding of CRP to PC moieties), but not soluble CRP, synergized with specific TLRs to posttranscriptionally amplify TNF, IL-1β, and IL-23 production by human inflammatory macrophages. We identified FcγRI and IIa as the main receptors responsible for initiating PC:CRP-induced inflammation. In addition, we identified the underlying mechanism, which depended on signaling through kinases Syk, PI3K, and AKT2, as well as glycolytic reprogramming. These data indicate that in humans, CRP is not only a marker but also a driver of inflammation by human macrophages. Therefore, although providing host defense against bacteria, PC:CRP-induced inflammation may also exacerbate pathology in the context of disorders such as atherosclerosis.
AB - C-reactive protein (CRP) is an acute-phase protein produced in high quantities by the liver in response to infection and during chronic inflammatory disorders. Although CRP is known to facilitate the clearance of cell debris and bacteria by phagocytic cells, the role of CRP in additional immunological functions is less clear. This study shows that complexed CRP (phosphocholine [PC]:CRP) (formed by binding of CRP to PC moieties), but not soluble CRP, synergized with specific TLRs to posttranscriptionally amplify TNF, IL-1β, and IL-23 production by human inflammatory macrophages. We identified FcγRI and IIa as the main receptors responsible for initiating PC:CRP-induced inflammation. In addition, we identified the underlying mechanism, which depended on signaling through kinases Syk, PI3K, and AKT2, as well as glycolytic reprogramming. These data indicate that in humans, CRP is not only a marker but also a driver of inflammation by human macrophages. Therefore, although providing host defense against bacteria, PC:CRP-induced inflammation may also exacerbate pathology in the context of disorders such as atherosclerosis.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85068428890&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31118224
U2 - https://doi.org/10.4049/jimmunol.1900172
DO - https://doi.org/10.4049/jimmunol.1900172
M3 - Article
C2 - 31118224
SN - 0022-1767
VL - 203
SP - 225
EP - 235
JO - Journal of immunology (Baltimore, Md.
JF - Journal of immunology (Baltimore, Md.
IS - 1
ER -