Plasma Pyruvate Kinase M2 as a marker of vascular inflammation in giant cell arteritis

Abstract

Objectives GCA is a large vessel vasculitis in which metabolically active immune cells play an important role. GCA diagnosis is based on CRP/ESR and temporal artery biopsies (TABs), in combination with 18F-fluorodeoxyglucose ([18F]FDG)-PET/CT relying on enhanced glucose uptake by glycolytic macrophages. Here, we studied circulating Pyruvate Kinase M2 (PKM2), a glycolytic enzyme, as a possible systemic marker of vessel wall inflammation in GCA. Methods Immunohistochemical detection of PKM2 was performed on inflamed (n = 12) and non-inflamed (n = 4) TABs from GCA patients and non-GCA (n = 9) patients. Dimeric PKM2 levels were assessed in plasma of GCA patients (n = 44), age-matched healthy controls (n = 41), metastatic melanoma patients (n = 7) and infection controls (n = 11). CRP, ESR and macrophage markers calprotectin and YKL-40 were correlated with plasma PKM2 levels. To detect the cellular source of plasma PKM2 in tissue, double IF staining was performed on inflamed GCA TABs. [18F]FDG-PET scans of 23 GCA patients were analysed and maximum standard uptake values and target to background ratios were calculated. Results PKM2 is abundantly expressed in TABs of GCA patients. Dimeric PKM2 plasma levels were elevated in GCA and correlated with CRP, ESR, calprotectin and YKL-40 levels. Elevated plasma PKM2 levels were downmodulated by glucocorticoid treatment. PKM2 was detected in both macrophages and T cells at the site of vascular inflammation. Circulating PKM2 levels correlated with average target to background ratios PET scores. Conclusion Elevated plasma PKM2 levels reflect active vessel inflammation in GCA and may assist in disease diagnosis and in disease monitoring.

Comment on: Plasma Pyruvate Kinase M2 as a marker of vascular inflammation in giant cell arteritis: reply

“…However, it has also been shown that inducing the tetrameric form of PKM2 via TEPP-46 suppresses pro-inflammatory responses by inhibiting IL-1ß production and inducing IL-10 [ 11 ]. In our study, we observed PKM2 expression in areas of IL-1ß+ macrophages and reported an association of PKM2 with other inflammatory and macrophage markers in both blood and tissue [ 2 ]. Therefore, we believe that TEPP-46 has potential as a therapeutic agent in GCA treatment.…”

“…Firstly, as pointed out by the authors, plasma PKM2 levels are indeed elevated not only in active GCA but also in malignancies and infections [ 2 ]. Thus, elevated PKM2 levels are not specific for GCA but rather reflect glycolytic inflammatory processes.…”

Metabolic features and glucocorticoid-induced comorbidities in patients with giant cell arteritis and polymyalgia rheumatica in a Dutch and Danish cohort

“…Additionally, our group recently demonstrated that the cellular glucose metabolism, that is, glycolytic activity, reflects systemic inflammation in patients with GCA, which may assist the diagnosis and monitoring of disease activity. 33 This may support an important link between disturbed glucose metabolism and inflammation in patients with GCA. However, the lack of association between glucose markers and inflammatory markers in patients with GCA argues against this conclusion.…”

Distinct gene signatures of monocytes and B cells in patients with giant cell arteritis: a longitudinal transcriptome analysis

“…Non-immune-mediated gene ontology terms associated with protein kinase A signaling, glucose and hexose transmembrane transports, cortical actin cytoskeleton organization, and mitochondrial ATP synthesis-coupled protein and glucose transports were all upregulated, while regulation associated with relaxation of cardiac muscle and cardiac muscle cell apoptotic process, hindlimb morphogenesis, inner ear receptor cell development, histone deacetylase activity, and muscle relaxation was downregulated in GCA. These may reflect the abnormalities of cellular metabolisms and cell development in GCA [ 14 , 44 , 45 ], although further investigations are needed.…”