P080 C-reactive protein: not only a marker, but also a cause of inflammation through metabolic reprogramming of human macrophages

Abstract

IntroductionC-reactive protein (CRP) is an acute-phase protein produced in high quantities by the liver in response to infection and during chronic inflammatory disorders such as rheumatoid arthritis (RA). As a consequence, CRP is in widespread clinical use as a general marker of inflammation. Although CRP is known to facilitate clearance of cell debris by phagocytic cells by binding to its ligand phosphocholine on dead cells, it is still unclear whether CRP displays additional immunological functions.ObjectivesHere, we set out to investigate whether CRP, which is present in high concentrations in synovial fluid of active RA patients, also plays a role in the orchestration of inflammation in the inflamed joint.MethodsHuman macrophages were differentiated from blood monocytes of healthy volunteers, or sorted from synovial fluid of RA patients. Cells were stimulated with complexed CRP (c-CRP) and/or ligands for Toll-like receptors (TLRs) and NOD-like receptors (NLRs), mimicking the stimuli in the inflamed joint. Responsible signalling pathways were identified using small molecule inhibitors and RNA interference. Metabolic pathways were identified using specific inhibitors and the Seahorse metabolic analyzer.ResultsStrikingly, we here provide evidence that CRP is not only a marker, but also a cause of inflammation by strongly amplifying the production of RA-associated pro-inflammatory cytokines. We show that complex formation of CRP as a result of binding to its ligand phosphocholine selectively enhanced TNFα, IL-1β, and IL-23 production by human macrophages. While c-CRP did not induce cytokine production individually, c-CRP synergized with TLRs and NLRs to amplify cytokine gene translation. We identified Fc gamma receptor I and IIa (FcγRI and FcγRIIa) as the main receptors responsible. Moreover, we unravelled the responsible molecular mechanism of c-CRP-induced inflammation, which crucially depends on signalling through kinases Syk and PI3K, resulting in enhanced gene translation of pro-inflammatory cytokines through metabolic reprogramming, particularly through amplified glycolysis and fatty acid synthesis.ConclusionsThese data indicate that CRP is not only a marker, but also a cause of inflammation in RA patients by selectively promoting RA-associated pro-inflammatory cytokine production by human macrophages, thereby exacerbating pathology. From a therapeutic point of view, inhibition of c-CRP-induced immune activation, e.g. by targeting the identified molecular mechanisms, may be a valuable tool to suppress inflammation.Disclosure of interestM. Newling: None declared, L. Sritharan: None declared, D. Baeten Employee of: Part-time employee UCB, J. Den Dunnen: None declared

Proteína 3 contendo um domínio NACHT, porção C-terminal rica em repetições de leucina e de domínio pirina e LL-37: valor prognóstico de novos biomarcadores em pneumonia adquirida na comunidade

“…C-reactive protein (CRP) is an acute-phase protein produced by hepatic cells that is widely involved in various inflammatory processes. (19) Serum CRP levels are generally low in healthy people, whereas stress stimulations such as infection and organ and tissue damage can trigger significant increase in serum CRP, which is typically not susceptible to antibiotics, malnutrition, glucocorticoids, or immunosuppressant drugs. (20) CRP is the most commonly used biomarker in the diagnosis and treatment of CAP due to its inexpensive price and high sensitivity to inflammation.…”

The role of TLR-2 and TLR-4 gene polymorphisms in the development of sepsis in children with severe burns

“…and methods: genetic analysis of TLR-2 Arg 753 Gln and TLR-4 Thr399 Ile gene polymorphisms was performed in children with severe and extremely severe burns (n = 22) who were treated in the anesthesiology department with intensive care beds. Results: as a result of the obtained data, the heterozygous genotype TLR-2 Arg 753 Gln was detected in 69.5% (n = 16), in 31.8% (n = 7) patients with burn injury polymorphism was not detected.…”