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DPP-4 Inhibitors Repress NLRP3 Inflammasome and Interleukin-1beta via GLP-1 Receptor in Macrophages Through Protein Kinase C Pathway

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Abstract

Background

Anti-atherosclerotic effects of dipeptidyl peptidase-4 (DPP-4) inhibitors have been shown in many studies. Since inflammation and immune response play a key role in atherogenesis, we examined the effect of DPP-4 inhibitors on the expression of nod-like receptor family, pyrin domain containing 3 (NLRP3) Inflammasome and Interleukin-1beta (IL-1β) in human macrophages.

Methods and Results

THP-1 macrophages were incubated with oxidized low density lipoprotein (ox-LDL) with or without DPP-4 inhibitors (sitagliptin and NVPDPP728). The effects of DPP-4 inhibitors on the expression of NLRP3, toll-like receptor 4 (TLR4) and pro-inflammatory cytokine IL-1β were studied. Both DPP-4 inhibitors induced a significant reduction in NLRP3, TLR4 and IL-1β expression; concurrently, there was an increase in glucagon like peptide 1 receptor (GLP-1R) expression. Simultaneously, DPP-4 inhibitors reduced phosphorylated-PKC, but not PKA, levels. To determine the role of PKC activation in the effects of DPP-4 inhibitors, cells were treated with PMA- which blocked the effect of DPP-4 inhibitors on NLRP3 and IL-1β as well as TLR4 and GLP-1R. Over-expression of GLP-1R in macrophages with its agonist liraglutide also blocked the effects of PMA.

Conclusion

DPP-4 inhibitors suppress NLRP3, TLR4 and IL-1β in human macrophages through inhibition of PKC activity. This study provides novel insights into the mechanism of inhibition of inflammatory state and immune response in atherosclerosis by DPP-4 inhibitors.

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References

  1. Ross R, Agius L. The process of atherogenesis–cellular and molecular interaction: from experimental animal models to humans. Diabetologia. 1992;35:S34–40.

    Article  PubMed  Google Scholar 

  2. Ishigaki Y, Katagiri H, Gao J, et al. Impact of plasma oxidized low-density lipoprotein removal on atherosclerosis. Circulation. 2008;118:75–83.

    Article  PubMed  CAS  Google Scholar 

  3. Masters SL, Dunne A, Subramanian SL, et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat Immunol. 2010;11:897–904.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  4. Pant S, Deshmukh A, Mehta JL. Inflammation and atherosclerosis—revisited. J Cardiovasc Pharmacol Ther. 2014;19:168–76.

    Article  Google Scholar 

  5. Satoh T, Kambe N, Matsue H. NLRP3 activation induces ASC-dependent programmed necrotic cell death, which leads to neutrophilic inflammation. Cell Death Dis. 2013;4:e644.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Jiang Y, Wang M, Huang K, et al. Oxidized low-density lipoprotein induces secretion of interleukin-1β by macrophages via reactive oxygen species-dependent NLRP3 inflammasome activation. Biochem Biophys Res Commun. 2012;425:121–6.

    Article  PubMed  CAS  Google Scholar 

  7. Liu W, Yin Y, Zhou Z, He M, Dai Y. OxLDL-induced IL-1beta secretion promoting foam cells formation was mainly via CD36 mediated ROS production leading to NLRP3 inflammasome activation. Inflamm Res. 2014;63:33–43.

    Article  PubMed  Google Scholar 

  8. Shiloh Y, Ziv Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol. 2013;14:197–210.

    Article  CAS  Google Scholar 

  9. Ma L, Dong F, Denis M, et al. Ht31, a protein kinase a anchoring inhibitor, induces robust cholesterol efflux and reverses macrophage foam cell formation through ATP-binding cassette transporter A1. J Biol Chem. 2011;286:3370–8.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Kong L, Shen X, Lin L, et al. PKCβ promotes vascular inflammation and acceleration of atherosclerosis in diabetic ApoE Null Mice. Arterioscler Thromb Vasc Biol. 2013;33:1779–87.

    Article  PubMed  CAS  Google Scholar 

  11. Ma L, Dong F, Zaid M, Kumar A, Zha X. ABCA1 protein enhances toll-like receptor 4 (TLR4)-stimulated interleukin-10 (IL-10) secretion through protein kinase a (PKA) activation. J Biol Chem. 2012;287:40502–12.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Namba M, Katsuno T, Kusunoki Y, et al. New strategy for the treatment of type 2 diabetes mellitus with incretin-based therapy. Clin Exp Nephrol. 2013;17:10–5.

    Article  PubMed  CAS  Google Scholar 

  13. Ervinna N, Mita T, Yasunari E, et al. Anagliptin, a DPP-4 inhibitor, suppresses proliferation of vascular smooth muscles and monocyte inflammatory reaction and attenuates atherosclerosis in male apo E-deficient mice. Endocrinology. 2013;154:1260–70.

    Article  PubMed  CAS  Google Scholar 

  14. Shah Z, Kampfrath T, Deiuliis JA, et al. Long-term dipeptidyl-peptidase 4 inhibition reduces atherosclerosis and inflammation via effects on monocyte recruitment and chemotaxis. Circulation. 2011;124:2338–49.

    Article  PubMed  CAS  Google Scholar 

  15. Matsubara J, Sugiyama S, Akiyama E, et al. Dipeptidyl peptidase-4 inhibitor, sitagliptin, improves endothelial dysfunction in association with its anti-inflammatory effects in patients with coronary artery disease and uncontrolled diabetes. Circ J. 2013;77:1337–44.

    Article  PubMed  CAS  Google Scholar 

  16. Krijnen PA, Hahn NE, Kholová I, et al. Loss of DPP4 activity is related to a prothrombogenic status of endothelial cells: implications for the coronary microvasculature of myocardial infarction patients. Basic Res Cardiol. 2012;107:233.

    Article  PubMed  Google Scholar 

  17. Park EK, Jung HS, Yang HI, et al. Optimized THP-1 differentiation is required for the detection of responses to weak stimuli. Inflamm Res. 2007;56:45–50.

    Article  PubMed  CAS  Google Scholar 

  18. Voloshyna I, Modayil S, Littlefield MJ, et al. Plasma from rheumatoid arthritis patients promotes pro-atherogenic cholesterol transport gene expression in THP-1 human macrophages. Exp Biol Med (Maywood). 2013;238:1192–7.

    Article  CAS  Google Scholar 

  19. Chua S, Sheu JJ, Chen YL, et al. Sitagliptin therapy enhances the number of circulating angiogenic cells and angiogenesis-evaluations in vitro and in the rat critical limb ischemia model. Cytotherapy. 2013;15:1148–63.

    Article  PubMed  CAS  Google Scholar 

  20. Dai Y, Mercanti F, Dai D, et al. LOX-1, a bridge between GLP-1R and mitochondrial ROS generation in human vascular smooth muscle cells. Biochem Biophys Res Commun. 2013;437:62–6.

    Article  PubMed  CAS  Google Scholar 

  21. Huang W, Ishii I, Zhang WY, Sonobe M, Kruth HS. PMA activation of macrophages alters macrophage metabolism of aggregated LDL. J Lipid Res. 2002;43:1275–82.

    PubMed  CAS  Google Scholar 

  22. Dai Y, Su W, Ding Z, et al. Regulation of MSR-1 and CD36 in macrophages by LOX-1 mediated through PPAR-γ. Biochem Biophys Res Commun. 2013;431:496–500.

    Article  PubMed  CAS  Google Scholar 

  23. Dai Y, Mehta JL, Chen M. Glucagon-like peptide-1 receptor agonist liraglutide inhibits endothelin-1 in endothelial cell by repressing nuclear factor-kappa B activation. Cardiovasc Drugs Ther. 2013;27:371–80.

    Article  PubMed  CAS  Google Scholar 

  24. Medzhitov R. Toll-like receptors and innate immunity. Nat Rev Immunol. 2001;1:135–45.

    Article  PubMed  CAS  Google Scholar 

  25. Terasaki M, Nagashima M, Nohtomi K, et al. Preventive effect of dipeptidyl peptidase-4 inhibitor on atherosclerosis is mainly attributable to Incretin’s actions in nondiabetic and diabetic apolipoprotein E-null mice. PLoS One. 2013;8:e70933.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Jose T, Inzucchi SE. Cardiovascular effects of the DPP-4 inhibitors. Diab Vasc Dis. 2012;9:109–16.

    Article  Google Scholar 

  27. Hayden JM, Reaven PD. Cardiovascular disease in diabetes mellitus type 2: a potential role for novel cardiovascular risk factors. Curr Opin Lipidol. 2000;11:519–28.

    Article  PubMed  CAS  Google Scholar 

  28. Ding Z, Liu S, Wang X, Khaidakov M, Dai Y, Mehta JL. Oxidant stress in mitochondrial DNA damage, autophagy and inflammation in atherosclerosis. Sci Rep. 2013;3:1077.

    PubMed  PubMed Central  Google Scholar 

  29. Lu X, Kakkar V. Inflammasome and atherogenesis. Curr Pharm Des. 2013 [Epub ahead of print]

  30. Manica-Cattani MF, Duarte MM, Ribeiro EE, de Oliveira R. Mânica da Cruz IB. Effect of the interleukin-1B gene on serum oxidized low-density lipoprotein levels. Clin Biochem. 2012;45:641–5.

    Article  PubMed  CAS  Google Scholar 

  31. Lundberg AM, Ketelhuth DF, Johansson ME, et al. Toll-like receptor 3 and 4 signalling through the TRIF and TRAM adaptors in haematopoietic cells promotes atherosclerosis. Cardiovasc Res. 2013;99:364–73.

    Article  PubMed  CAS  Google Scholar 

  32. Blich M, Golan A, Arvatz G, et al. Macrophage activation by heparanase is mediated by TLR-2 and TLR-4 and associates with plaque progression. Arterioscler Thromb Vasc Biol. 2013;33:e56–65.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Liu R, He Y, Li B, et al. Tenascin-C produced by oxidized LDL-stimulated macrophages increases foam cell formation through Toll-like receptor-4. Mol Cells. 2012;34:35–41.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Xu XH, Shah PK, Faure E, et al. Toll-like receptor-4 is expressed by macrophages in murine and human lipid-rich atherosclerotic plaques and upregulated by oxidized LDL. Circulation. 2001;104:3103–8.

    Article  PubMed  CAS  Google Scholar 

  35. Kaur H, Chien A, Jialal I. Hyperglycemia induces toll like receptor 4 expression and activity in mouse mesangial cells: relevance to diabetic nephropathy. Am J Physiol Renal Physiol. 2012;303:F1145–50.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  36. Wardill HR, Gibson RJ, Logan RM, Bowen JM. TLR4/PKC-mediated tight junction modulation: a clinical marker of chemotherapy-induced gut toxicity? Int J Cancer. 2013 Dec 6. doi: 10.1002/ijc.28656. [Epub ahead of print]

  37. Qu Y, Misaghi S, Izrael-Tomasevic A, et al. Phosphorylation of NLRC4 is critical for inflammasome activation. Nature. 2012;490:539–42.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported in part by funds from the department of veterans affairs, veterans health administration, office of research and development, biomedical laboratory research and development, Washington, DC; additional support was provided by the national natural science foundation for fostering young scholars of china (the first hospital of Anhui medical university, grant No. 2013KJ25).

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Correspondence to Dongsheng Dai or Jawahar L. Mehta.

Additional information

Y. Dai and D. Dai contributed equally to this study and should be considered co-first authors.

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Dai, Y., Dai, D., Wang, X. et al. DPP-4 Inhibitors Repress NLRP3 Inflammasome and Interleukin-1beta via GLP-1 Receptor in Macrophages Through Protein Kinase C Pathway. Cardiovasc Drugs Ther 28, 425–432 (2014). https://doi.org/10.1007/s10557-014-6539-4

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