Homocysteine Activates B Cells via Regulating PKM2-Dependent Metabolic Reprogramming

Abstract

The overactivation of immune cells plays an important role in the pathogenesis of hyperhomocysteinemia (HHcy)-accelerated atherosclerosis. Homocysteine (Hcy) activates B cell proliferation and Ab secretion; however, the underlying mechanisms for these effects remain largely unknown. Metabolic reprogramming is critical for lymphocyte activation and effector function. In this study, we showed that Hcy-activated B cells displayed an increase in both oxidative phosphorylation and glycolysis, with a tendency to shift toward the latter, as well as an accumulation of intermediates in the pentose phosphate pathway, to provide energy and biosynthetic substrates for cell growth and function. Mechanistically, Hcy increased both the protein expression and glycolytic enzyme activity of the pyruvate kinase muscle isozyme 2 (PKM2) in B cells, whereas the PKM2 inhibitor shikonin restored Hcy-induced metabolic changes, as well as B cell proliferation and Ab secretion both in vivo and in vitro, indicating that PKM2 plays a critical role in metabolic reprogramming in Hcy-activated B cells. Further investigation revealed that the Akt–mechanistic target of rapamycin signaling pathway was involved in this process, as the mechanistic target of rapamycin inhibitor rapamycin inhibited Hcy-induced changes in PKM2 enzyme activity and B cell activation. Notably, shikonin treatment effectively attenuated HHcy-accelerated atherosclerotic lesion formation in apolipoprotein E–deficient mice. In conclusion, our results demonstrate that PKM2 is required to support metabolic reprogramming for Hcy-induced B cell activation and function, and it might serve as a critical regulator in HHcy-accelerated initiation of atherosclerosis.

Initial B Cell Activation Induces Metabolic Reprogramming and Mitochondrial Remodeling

“…Accumulation of 3PG may also suggest a block in pyruvate kinase ( Pkm1 ), which catalyzes the conversion of phosphoenol pyruvate to pyruvate, or a switch to expression of the pyruvate kinase 2 ( Pkm2 ) isoform. This switch has previously been observed in homocysteine-stimulated B cells (Deng et al., 2017) and occurs commonly in proliferating cells with a high level of nucleotide biosynthesis (Dayton et al., 2016). …”

Targeting immunometabolism as an anti-inflammatory strategy

“…111 Evidence for a role for PKM2 in B cell mediated pathology comes from a model of hyperhomocysteinemia (HHcy)-accelerated atherosclerosis where homocysteine activated B cells display an increase in glycolysis, coupled to an upregulation of PKM2. 155 Shikonin, an inhibitor of PKM2, restored homocysteine-induced B cell proliferation as well as antibody secretion both in vitro and in vivo, and reduced HHcyaccelerated atherosclerotic lesion formation.…”

Hyperhomocysteinaemia and vascular injury: advances in mechanisms and drug targets

“…Inhibition of the trans‐sulphuration pathway by propargylglycine impairs pathogen clearance by macrophages (Garg et al ., ). Recently, pyruvate kinase 2‐dependent metabolic reprogramming has been demonstrated to mediate proliferation and IgG secretion of B cells induced by homocysteine and HHcy‐exacerbated atherosclerosis (Deng et al ., ). In apolipoprotein E‐deficient (ApoE −/− ) mice with HHcy, treatment with CTLA4‐IgG attenuated the atherosclerotic lesions, by competing with CD28 to inhibit T‐lymphocyte overactivation (Ma et al ., ).…”