Promotion of Calcium/Calmodulin‐Dependent Protein Kinase 4 by GLUT1‐Dependent Glycolysis in Systemic Lupus Erythematosus

Abstract

Objective. To clarify the significance of immunometabolism in systemic lupus erythematosus (SLE), and to determine the effect of calcium/calmodulin-dependent protein kinase 4 (CaMK4) on T cell metabolism.Methods. Metabolomic profiling was performed using capillary electrophoresis mass spectrometry in naive T cells from MRL/lpr mice treated with anti-CD3/CD28 antibodies in the absence or presence of a CaMK4 inhibitor (KN-93). The expression of GLUT1 and CaMK4 in CD4+ T cells from healthy controls (n = 16), patients with inactive SLE (n = 13), and patients with active SLE (n = 14) was examined by flow cytometry and quantitative polymerase chain reaction. In vitro experiments were performed to determine the effect of KN-93 on the expression of GLUT1 during Th17 cell differentiation in T cells from patients with SLE.Results. CaMK4 inhibition significantly decreased the levels of glycolytic intermediates such as glucose-6-phosphate, fructose-6-phosphate, fructose-1,6-diphosphate, pyruvate, and lactate (P < 0.05), whereas it did not affect the levels of the pentose phosphate pathway intermediates such as 6-phosphod-gluconate, ribulose-5-phosphate, ribose-5-phosphate, and phosphoribosyl pyrophosphate. The expression levels of GLUT1 and CaMK4 in effector memory CD4+ T cells were significantly higher in patients with active SLE compared to healthy controls (P < 0.01 and P < 0.05, respectively) and patients with inactive SLE (P < 0.05 and P < 0.01, respectively). A functional analysis revealed that CaMK4 inhibition decreased the expression of GLUT1 during Th17 cell differentiation (P < 0.01), followed by a reduction of interleukin-17 (IL-17) production (P < 0.05).Conclusion. The results of the study indicate that the activity of CaMK4 could be responsible for glycolysis, which contributes to the production of IL-17, and CaMK4 may contribute to aberrant expression of GLUT1 in T cells from patients with active SLE.

Glucose transporter 1 in rheumatoid arthritis and autoimmunity

“…Glucose needs to be transported into the cell to enable this process and the identification of GLUT1 as main glucose transporter in lymphocytes and myeloid cells translated these metabolic changes into first potential targets. Interestingly, increased glucose uptake, glycolysis, and GLUT1 expression could be confirmed in human RA, SLE, and psoriasis patients (Biniecka et al, ; Koga et al, ; Zhang et al, ) and similar effects were seen in corresponding autoimmune mouse models (Freitag et al, ; Rhoads et al, ). GLUT1 level and glucose uptake often correlate with disease scores or treatment response in human trials, suggesting a potential as novel biomarker.…”

Metabolic determinants of lupus pathogenesis

“…Moreover, CaMK4 inhibition decreased the production of glycolytic intermediates by activated CD4 + T cells from MRL/lpr lupus-prone mice. 35 These results showed a functional link between CaMK4 and glycolysis in T cells and suggest that the beneficial effect of CaMK4 inhibition in lupus 36 may be due at least in part through the mitigation of immunometabolism.…”

“…156 Although overexpression of Glut1 in mice was not sufficient to induce lupus, SLE patients with active disease present a higher GLUT1 on effector memory CD4 + T cells as compared to either HCs or patients with inactive disease, and this elevated GLUT1 level was associated with an elevated expression of calcium/calmodulin-dependent protein kinase 4 (CaMK4). 35 CaMK4 is a major regulator of pathogenic T cells in lupus through its regulation of IL-2 and IL-17 expression. 33 Accordingly, the polarization of human Th17 cells, an effector subset that is highly dependent of glycolysis, 30 was reduced by CaMK4 inhibition, which reduced GLUT1 expression.…”

T cell Metabolism in Lupus

“…Therefore, enhanced secondary glycolysis is observed in SLE[71].Overexpression of Glut1 in murine T cells results in the development of lupus-like disease in older mice and selective accumulation of effector and follicular T cells[72]. More recently, Glut1 overexpression was found in effector memory CD4 + T cells in people with active and inactive SLE[73].Increased Glut1 expression can be reversed by inhibiting the T cellImmunometabolism. 2020;2(2):e200009.…”

“…2020;2(2):e200009. https://doi.org/10.20900/immunometab20200009 Immunometabolism 7 of 19 restricted serine/threonine kinase, calcium/calmodulin-dependent protein kinase IV (CaMK4) which is overexpressed in SLE T cells[73,74].Pharmacological inhibition or genetic deletion of CaMK4 decreases glycolysis and ameliorates disease activity in MRL/lpr mice[75][76][77]. CaMK4 activates AKT/mTOR pathway but is also found to promote glycolysis by binding and augmenting the activity of pyruvate kinase M2, the final ratelimiting enzyme in glycolysis, underlying autoimmunity associated with Th17 in SLE[78,79].…”