Intermittent hyperglycaemia induces macrophage dysfunction by extracellular regulated protein kinase-dependent PKM2 translocation in periodontitis

Abstract

Early fluctuations in blood glucose levels increased susceptibility to macrophage dysfunction. However, the underlying pathological mechanisms linking glucose variations and macrophage dysregulation remains elusive. In current study, we established an animal model of transient intermittent hyperglycaemia (TIH) to simulate early fluctuations in blood glucose levels. Our findings revealed that both TIH and diabetic group exhibited more severe periodontal lesions and increased secretion of pro-inflammatory cytokines compared to healthy controls. In immortalized bone marrow–derived macrophages (iBMDMs), phagocytosis and chemotaxis were impaired with transient and lasting hyperglycaemia, accompanied by enhanced glycolysis. We also found that TIH activated pyruvate kinase M2 (PKM2) through the phosphorylation of extracellular regulated protein kinase (ERK) in vivo, particularly at dimeric levels. In macrophage cultured with TIH, PKM2 translocated into the nucleus and involved in the regulating inflammatory genes, including TNF-α, IL-6 and IL-1β. PKM2 translocation and secretion of inflammatory cytokines were attenuated by PD98059, while PKM2 tetramer activator TEPP-46 prevented the formation of dimeric PKM2 in macrophages. Moreover, inhibition of glycolysis alleviated the TIH-induced pro-inflammatory cytokines. In conclusion, our manuscript provides a rationale for understanding how TIH modulates metabolic rewiring and dysfunction in macrophages via ERK-dependent PKM2 nuclear translocation.

References

[1] KocherT, König J, BorgnakkeWS, PinkC, MeiselP. Periodontal complications of hyperglycemia/diabetes mellitus: epidemiologic complexity and clinical challenge. Diabetes Care. 2018;78(1):59-97.

[2] van DamE, van Leeuwen LAG, Dos SantosE, et al. Sugar-induced obesity and insulin resistance are uncoupled from shortened survival in drosophila. Cell Metab. 2020;31(4):710-725.e717.

[3] ZhangP, WangQ, NieL, et al. Hyperglycemia-induced inflamm-aging accelerates gingival senescence via nlrc4 phosphorylation. J Biol Chem. 2019;294(49):18807-18819.

[4] ZhaoP, YueZ, NieL, et al. Hyperglycaemia-associated macrophage pyroptosis accelerates periodontal inflamm-aging. J Clin Periodontol. 2021;48(10):1379-1392.

[5] D’AiutoF, Gkranias N, BhowruthD, et al. Systemic effects of periodontitis treatment in patients with type 2 diabetes: a 12 month, single-centre, investigator-masked, randomised trial. Lancet Diabetes Endocrinol. 2018;6(12):954-965.

[6] FlynnMC, Kraakman MJ, TikellisC, et al. Transient intermittent hyperglycemia accelerates atherosclerosis by promoting myelopoiesis. Circ Res. 2020;127(7):877-892.

[7] BebuI, Braffett BH, de BoerIH, et al. Relationships between the cumulative incidences of long-term complications in type 1 diabetes: the DCCT/Edic study. Diabetes Care. 2023;46(2):361-368.

[8] LindM, ImbergH, ColemanRL, Nerman O, HolmanRR. Historical hba(1c) values may explain the type 2 diabetes legacy effect: Ukpds 88. Diabetes Care. 2021;44(10):2231-2237.

[9] ChengSC, Quintin J, CramerRA, et al. Mtor-and hif-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science. 2014;345(6204):1250684.

[10] NeteaMG, Joosten LA, LatzE, et al. Trained immunity: a program of innate immune memory in health and disease. Science. 2016;352(6284):aaf1098.

[11] YangW, ZhengY, XiaY, et al. Erk1/2-dependent phosphorylation and nuclear translocation of pkm2 promotes the warburg effect. Nat Cell Biol. 2012;14(12):1295-1304.

[12] AngiariS, Runtsch MC, SuttonCE, et al. Pharmacological activation of pyruvate kinase m2 inhibits cd4(+) t cell pathogenicity and suppresses autoimmunity. Cell Metab. 2020;31(2):391-405.e398.

[13] DoddapattarP, DevR, GhatgeM, et al. Myeloid cell pkm2 deletion enhances efferocytosis and reduces atherosclerosis. Circ Res. 2022;130(9):1289-1305.

[14] Palsson-McDermottEM, Curtis AM, GoelG, et al. Pyruvate kinase m2 regulates hif-1α activity and il-1β induction and is a critical determinant of the warburg effect in lps-activated macrophages. Cell Metab. 2015;21(1):65-80.

[15] WangJ, YangP, YuT, et al. Lactylation of pkm2 suppresses inflammatory metabolic adaptation in pro-inflammatory macrophages. Int J Biol Sci. 2022;18(16):6210-6225.

[16] WangP, SunC, ZhuT, XuY. Structural insight into mechanisms for dynamic regulation of pkm2. Protein Cell. 2015;6(4):275-287.

[17] WongTL, NgKY, TanKV, et al. Craf methylation by prmt6 regulates aerobic glycolysis-driven hepatocarcinogenesis via erk-dependent pkm2 nuclear relocalization and activation. Hepatology. 2020;71(4):1279-1296.

[18] MarinoF, Scalise M, SalernoN, et al. Diabetes-induced cellular senescence and senescence-associated secretory phenotype impair cardiac regeneration and function independently of age. Diabetes. 2022;71(5):1081-1098.

[19] ShiraiT, Nazarewicz RR, WallisBB, et al. The glycolytic enzyme pkm2 bridges metabolic and inflammatory dysfunction in coronary artery disease. J Exp Med. 2016;213(3):337-354.

[20] XieM, YuY, KangR, et al. Pkm2-dependent glycolysis promotes nlrp3 and aim2 inflammasome activation. Nat Commun. 2016;7:13280.

[21] WuY, WangY, YaoH, et al. Mnx1-as1, a c-myc induced lncrna, promotes the warburg effect by regulating pkm2 nuclear translocation. J Exp Clin Cancer Res. 2022;41(1):337.

[22] WangW, ZhengH, JiangJ, et al. Engineering micro oxygen factories to slow tumour progression via hyperoxic microenvironments. Nat Commun. 2022;13(1):4495.

[23] GaoS, LiX, JiangQ, et al. Pkm2 promotes pulmonary fibrosis by stabilizing tgf-β1 receptor i and enhancing tgf-β1 signaling. Sci Adv. 2022;8:eabo0987.

[24] SiM, WangQ, LiY, et al. Inhibition of hyperglycolysis in mesothelial cells prevents peritoneal fibrosis. Sci Transl Med. 2019;11(495):eaav5341.

[25] WangQ, NieL, ZhaoP, et al. Diabetes fuels periodontal lesions via glut1-driven macrophage inflammaging. Int J Oral Sci. 2021;13(1):11.

[26] ZhouX, ZhangP, WangQ, et al. Metformin ameliorates experimental diabetic periodontitis independently of mammalian target of rapamycin (mtor) inhibition by reducing nima-related kinase 7 (nek7) expression. J Periodontol. 2019;90(9):1032-1042.

[27] ChristA, Günther P, LauterbachMAR, et al. Western diet triggers nlrp3-dependent innate immune reprogramming. Cell. 2018;172(1–2):162-175.e114.

[28] CerielloA, Prattichizzo F, PhillipM, HirschIB, Mathieu C, BattelinoT. Glycaemic management in diabetes: old and new approaches. Lancet Diabetes Endocrinol. 2022;10(1):75-84.

[29] ChoudhuryRP. Transient intermittent hyperglycemia-enhanced myelopoiesis and atherosclerosis: short and sweet. Circ Res. 2020;127(7):893-895.

[30] KatoM, Natarajan R. Epigenetics and epigenomics in diabetic kidney disease and metabolic memory. Nat Rev Nephrol. 2019;15(6):327-345.

[31] NaikS, FuchsE. Inflammatory memory and tissue adaptation in sickness and in health. Nature. 2022;607(7918):249-255.

[32] ShenZ, KuangS, ZhangM, et al. Inhibition of ccl2 by bindarit alleviates diabetes-associated periodontitis by suppressing inflammatory monocyte infiltration and altering macrophage properties. Cell Mol Immunol. 2021;18(9):2224-2235.

[33] NieL, ZhaoP, YueZ, et al. Diabetes induces macrophage dysfunction through cytoplasmic dsdna/aim2 associated pyroptosis. J Leukoc Biol. 2021;110(3):497-510.

[34] FordeAJ, KolterJ, ZwickyP, et al. Metabolic rewiring tunes dermal macrophages in staphylococcal skin infection. Sci Immunol. 2023;8:eadg3517.

[35] ZhangB, YangY, YiJ, ZhaoZ, YeR. Hyperglycemia modulates m1/m2 macrophage polarization via reactive oxygen species overproduction in ligature-induced periodontitis. J Periodontal Res. 2021;56(5):991-1005.

[36] DamascenoLEA, PradoDS, VerasFP, et al. Pkm2 promotes th17 cell differentiation and autoimmune inflammation by fine-tuning STAT3 activation. J Exp Med. 2020;217(10):e20190613.

[37] YangL, XieM, YangM, et al. Pkm2 regulates the warburg effect and promotes hmgb1 release in sepsis. Nat Commun. 2014;5:4436.

[38] QiW, KeenanHA, LiQ, et al. Pyruvate kinase m2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction. Nat Med. 2017;23(6):753-762.

[39] Moreno-FernandezME, Giles DA, OatesJR, et al. Pkm2-dependent metabolic skewing of hepatic th17 cells regulates pathogenesis of non-alcoholic fatty liver disease. Cell Metab. 2021;33(6):1187-1204.e1189.

RIGHTS & PERMISSIONS

2024 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.