Research Article

Phospholipids impact the protective effects of HDL-mimetic nanodiscs against lipopolysaccharide-induced inflammation

https://orcid.org/0000-0002-5781-9039

Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48105, USA

Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA

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Jukyung Kang

https://orcid.org/0000-0002-2592-9401

Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48105, USA

Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA

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Maria V Fawaz

https://orcid.org/0000-0002-4743-1444

Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA

Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48105, USA

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Minzhi Yu

https://orcid.org/0000-0002-3141-7285

Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48105, USA

Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA

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Ziyun Xia

https://orcid.org/0000-0002-6409-1517

Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48105, USA

Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA

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Emily E Morin

https://orcid.org/0000-0001-5253-2074

Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48105, USA

Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA

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Ling Mei

https://orcid.org/0000-0002-2762-2235

Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48105, USA

Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA

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Karl Olsen

Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48105, USA

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Xiang-An Li

https://orcid.org/0000-0002-6899-7332

Department of Physiology, Saha Cardiovascular Research Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA

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Anna Schwendeman

*Author for correspondence:

E-mail Address: annaschw@umich.edu

https://orcid.org/0000-0002-8023-8080

Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48105, USA

Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA

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Published Online:10 Jan 2024https://doi.org/10.2217/nnm-2023-0222

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Abstract

Aim: The impacts of synthetic high-density lipoprotein (sHDL) phospholipid components on anti-sepsis effects were investigated. Methods: sHDL composed with ApoA-I mimetic peptide (22A) and different phosphatidylcholines were prepared and characterized. Anti-inflammatory effects were investigated in vitro and in vivo on lipopolysaccharide (LPS)-induced inflammation models. Results: sHDLs composed with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (22A-DMPC) most effectively neutralizes LPS, inhibits toll-like receptor 4 recruitment into lipid rafts, suppresses nuclear factor κB signaling and promotes activating transcription factor 3 activating. The lethal endotoxemia animal model showed the protective effects of 22A-DMPC. Conclusion: Phospholipid components affect the stability and fluidity of nanodiscs, impacting the anti-septic efficacy of sHDLs. 22A-DMPC presents the strongest LPS binding and anti-inflammatory effects in vitro and in vivo, suggesting a potential sepsis treatment.

Plain language summary

Sepsis is triggered by endotoxins released by bacteria. These endotoxins trigger an exaggerated inflammatory response, leading to widespread inflammation and organ damage. Synthetic high-density lipoprotein (sHDL) is a potential treatment of sepsis by neutralizing endotoxins and regulating inflammatory responses. The phospholipid components of sHDL may affect the effectiveness of sHDL against sepsis. In this study, we prepared sHDLs with different phospholipids and compared their anti-septic effects on cells and in animal models. We found that sHDL made from DMPC presented the best anti-septic effects, possibly because DMPC-sHDL had the best fluidity at body temperature.

Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. Singer M, Deutschman CS, Seymour CW et al. The Third International Consensus Definitions for sepsis and septic shock (sepsis-3). JAMA 315(8), 801–810 (2016).
Medline CASGoogle Scholar
2. Medzhitov R, Janeway C Jr. Innate immunity. NEJM 343(5), 338–344 (2000).
Medline CASGoogle Scholar
3. Poltorak A, He X, Smirnova I et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282(5396), 2085–2088 (1998).
Medline CASGoogle Scholar
4. Maeshima N, Fernandez RC. Recognition of lipid A variants by the TLR4-MD-2 receptor complex. Front. Cell. Infect. Microbiol. 3, 3 (2013).
MedlineGoogle Scholar
5. Lu YC, Yeh WC, Ohashi PS. LPS/TLR4 signal transduction pathway. Cytokine 42(2), 145–151 (2008).
Medline CASGoogle Scholar
6. Pirillo A, Catapano AL, Norata GD. HDL in infectious diseases and sepsis. Handb. Exp. Pharmacol. 224, 483–508 (2015).
Medline CASGoogle Scholar
7. Guo L, Zheng Z, Ai JT, Huang B, Li XA. Hepatic scavenger receptor BI protects against polymicrobial-induced sepsis through promoting LPS clearance in mice. J. Biol. Chem. 289(21), 14666–14673 (2014).
Medline CASGoogle Scholar
8. Zhu XW, Owen JS, Wilson MD et al. Macrophage ABCA1 reduces MyD88-dependent Toll-like receptor trafficking to lipid rafts by reduction of lipid raft cholesterol. J. Lipid Res. 51(11), 3196–3206 (2010).
Medline CASGoogle Scholar
9. De Nardo D, Labzin LI, Kono H et al. High-density lipoprotein mediates anti-inflammatory reprogramming of macrophages via the transcriptional regulator ATF3. Nat. Immunol. 15(2), 152–160 (2014). •• It is a publication that discusses the relationship between high-density lipoprotein (HDL) and ATF3 inducing the anti-inflammatory property, one of the key mechanisms of action we explore in the manuscript.
MedlineGoogle Scholar
10. Wang Y, Wang YH, Jia SY et al. Effect of lipid-bound apolipoprotein A-I cysteine mutant on ATF3 in RAW264.7 cells. Biosci. Rep. 37, BSR20160398 (2017).
Medline CASGoogle Scholar
11. Smith CK, Seto NL, Vivekanandan-Giri A et al. Lupus high-density lipoprotein induces proinflammatory responses in macrophages by binding lectin-like oxidised low-density lipoprotein receptor 1 and failing to promote activating transcription factor 3 activity. Ann. Rheum. Dis. 76(3), 602–611 (2017).
Medline CASGoogle Scholar
12. Chien JY, Jerng JS, Yu CJ. Low serum level of high-density lipoprotein cholesterol is a poor prognostic factor for severe sepsis. Crit. Care Med. 33(8), 1688–1693 (2005).
Medline CASGoogle Scholar
13. Tsai MH, Peng YS, Chen YC et al. Low serum concentration of apolipoprotein A-I is an indicator of poor prognosis in cirrhotic patients with severe sepsis. J. Hepatol. 50(5), 906–915 (2009).
Medline CASGoogle Scholar
14. van Leeuwen HJ, Heezius ECJM, Dallinga GM, van Strijp JAG, Verhoef J, van Kessel KPM. Lipoprotein metabolism in patients with severe sepsis. Crit. Care Med. 31(5), 1359–1366 (2003).
Medline CASGoogle Scholar
15. Morin EE, Guo L, Schwendeman A, Li XA. HDL in sepsis - risk factor and therapeutic approach. Front. Pharmacol. 6, 244 (2015).
MedlineGoogle Scholar
16. Tanaka S, Couret D, Tran-Dinh A et al. High-density lipoproteins during sepsis: from bench to bedside. Crit. Care 24(1), 1–11 (2020).
MedlineGoogle Scholar
17. Pajkrt D, Doran JE, Koster F et al. Anti-inflammatory effects of reconstituted high-density lipoprotein during human endotoxemia. J. Exp. Med. 184(5), 1601–1608 (1996).
Medline CASGoogle Scholar
18. Guo L, Morin EE, Yu MZ et al. Replenishing HDL with synthetic HDL has multiple protective effects against sepsis in mice. Sci. Signal 15(725), eabl9322 (2022). • It is a publication previously published by our group on the potential benefit of synthetic high-density lipoprotein (sHDL) nanodisc to improve survival from septic mice by neutralizing endotoxin and suppressing the inflammatory markers.
Medline CASGoogle Scholar
19. Fawaz MV, Kim SY, Li D et al. Phospholipid component defines pharmacokinetic and pharmacodynamic properties of synthetic high-density lipoproteins. J. Pharmacol. Exp. Ther. 372(2), 193–204 (2020). • It is a publication previously published by our group evaluating the physicochemical properties and PK/PD profiles of sHDL nanodisc used in this manuscript.
Medline CASGoogle Scholar
20. Schwendeman A, Sviridov DO, Yuan W et al. The effect of phospholipid composition of reconstituted HDL on its cholesterol efflux and anti-inflammatory properties. J. Lipid Res. 56(9), 1727–1737 (2015). • It is a publication previously published by our group proposing that phospholipid composition, not the peptide, of sHDL nanodisc plays a critical role in its anti-inflammatory properties.
Medline CASGoogle Scholar
21. Thoolen B, Maronpot RR, Harada T et al. Proliferative and nonproliferative lesions of the rat and mouse hepatobiliary system. Toxicol. Pathol. 38(Suppl. 7), S5–S81 (2010).
Google Scholar
22. Giebeler A, Streetz KL, Soehnlein O, Neumann U, Wang JM, Brandenburg LO. Deficiency of formyl peptide receptor 1 and 2 is associated with increased inflammation and enhanced liver injury after LPS-stimulation. PLOS ONE 9(6), e100522 (2014).
MedlineGoogle Scholar
23. Hamesch K, Borkham-Kamphorst E, Strnad P, Weiskirchen R. Lipopolysaccharide-induced inflammatory liver injury in mice. Lab Anim.-UK 49, 37–46 (2015).
Medline CASGoogle Scholar
24. de Souza Xavier Costa N, Ribeiro G, Dos Santos Alemany AA et al. Early and late pulmonary effects of nebulized LPS in mice: an acute lung injury model. PLOS ONE 12(9), e0185474 (2017).
MedlineGoogle Scholar
25. Kim YH, Yoon DW, Kim JH, Lee JH, Lim CH. Effect of remote ischemic post-conditioning on systemic inflammatory response and survival rate in lipopolysaccharide-induced systemic inflammation model. J. Inflamm-Lond. 11, 1–9 (2014).
MedlineGoogle Scholar
26. Tang J, Li D, Drake L et al. Influence of route of administration and lipidation of apolipoprotein A-I peptide on pharmacokinetics and cholesterol mobilization. J. Lipid Res. 58(1), 124–136 (2017).
Medline CASGoogle Scholar
27. Li D, Fawaz MV, Morin EE et al. Effect of synthetic high density lipoproteins modification with polyethylene glycol on pharmacokinetics and pharmacodynamics. Mol. Pharmaceut. 15(1), 83–96 (2018).
Medline CASGoogle Scholar
28. Boulgaropoulos B, Arsov Z, Laggner P, Pabst G. Stable and Unstable lipid domains in ceramide-containing membranes. Biophys. J. 100(9), 2160–2168 (2011).
Medline CASGoogle Scholar
29. Rowe ES. Lipid chain-length and temperature-dependence of ethanol phosphatidylcholine interactions. Biochemistry US 22(14), 3299–3305 (1983).
CASGoogle Scholar
30. Ulevitch RJ, Johnston AR. The modification of biophysical and endotoxic properties of bacterial lipopolysaccharides by serum. J. Clin. Invest. 62(6), 1313–1324 (1978).
Medline CASGoogle Scholar
31. Wurfel MM, Hailman E, Wright SD. Soluble Cd14 acts as a shuttle in the neutralization of lipopolysaccharide (LPS) by lps-binding protein and reconstituted high-density-lipoprotein. J. Exp. Med. 181(5), 1743–1754 (1995).
Medline CASGoogle Scholar
32. Levine DM, Parker TS, Donnelly TM, Walsh A, Rubin AL. In-vivo protection against endotoxin by plasma high-density-lipoprotein. P. Natl Acad. Sci. USA 90(24), 12040–12044 (1993).
Medline CASGoogle Scholar
33. Whitmore MM, Iparraguirre A, Kubelka L, Weninger W, Hai T, Williams BR. Negative regulation of TLR-signaling pathways by activating transcription factor-3. J. Immunol. 179(6), 3622–3630 (2007).
Medline CASGoogle Scholar
34. Gilchrist M, Thorsson V, Li B et al. Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4. Nature 441(7090), 173–178 (2006).
Medline CASGoogle Scholar
35. Guo Y, Yuan W, Yu B et al. Synthetic high-density lipoprotein-mediated targeted delivery of liver X receptors agonist promotes atherosclerosis regression. EBioMedicine 28, 225–233 (2018).
MedlineGoogle Scholar
36. He H, Halseth TA, Mei L, Shen C, Liu L, Schwendeman A. Nanodisc delivery of liver X receptor agonist for the treatment of diabetic nephropathy. J. Control. Rel. 348, 1016–1027 (2022).
Medline CASGoogle Scholar
37. Capodanno D, Mehran R, Gibson CM, Angiolillo DJ. CSL112, a reconstituted, infusible, plasma-derived apolipoprotein A-I: safety and tolerability profiles and implications for management in patients with myocardial infarction. Expert. Opin. Investig. Drugs 27(12), 997–1005 (2018).
Medline CASGoogle Scholar
38. Michael Gibson C, Korjian S, Tricoci P et al. Safety and tolerability of CSL112, a reconstituted, infusible, plasma-derived apolipoprotein A-I, after acute myocardial infarction: the AEGIS-I trial (ApoA-I Event Reducing in Ischemic Syndromes I). Circulation 134(24), 1918–1930 (2016).
MedlineGoogle Scholar
39. Zhang C, Li Q, Shan J et al. Multifunctional two-dimensional Bi₂Se₃ nanodiscs for anti-inflammatory therapy of inflammatory bowel diseases. Acta Biomater. 160, 252–264 (2023).
Medline CASGoogle Scholar
40. Jin X, Zhang W, Shan J et al. Thermosensitive hydrogel loaded with nickel–copper bimetallic hollow nanospheres with SOD and CAT enzymatic-like activity promotes acute wound healing. ACS Appl. Mater. Interfaces. 14(45), 50677–50691 (2022).
Medline CASGoogle Scholar
41. Gui S, Tang W, Huang Z et al. Ultrasmall coordination polymer nanodots Fe-Quer nanozymes for preventing and delaying the development and progression of diabetic retinopathy. Adv. Funct. Mater. 33, 2300261 (2023).
Google Scholar
42. Liu D, Dai X, Zhang W et al. Liquid exfoliation of ultrasmall zirconium carbide nanodots as a noninflammatory photothermal agent in the treatment of glioma. Biomaterials 292, 121917 (2023).
Medline CASGoogle Scholar
43. Yan YJ, Li Y, Lou B, Wu MP. Beneficial effects of ApoA-I on LPS-induced acute lung injury and endotoxemia in mice. Life Sci. 79(2), 210–215 (2006).
Medline CASGoogle Scholar
44. Zhang X, Wang L, Chen B. Recombinant HDL (Milano) protects endotoxin-challenged rats from multiple organ injury and dysfunction. Biol. Chem. 396(1), 53–60 (2015).
Medline CASGoogle Scholar
45. Wang Y, Zhu X, Wu G, Shen L, Chen B. Effect of lipid-bound apoA-I cysteine mutants on lipopolysaccharide-induced endotoxemia in mice. J. Lipid Res. 49(8), 1640–1645 (2008).
Medline CASGoogle Scholar
46. Patel H, Ding B, Ernst K et al. Characterization of apolipoprotein A-I peptide phospholipid interaction and its effect on HDL nanodisc assembly. Int. J. Nanomed. 14, 3069–3086 (2019). •• It is a publication that discusses how temperature can affect the fluidity and instability of phospholipid membrane during the sHDL nanodisc synthesis.
Medline CASGoogle Scholar
47. Bonnefontrousselot D, Motta C, Khalil AO et al. Physicochemical changes in human high-density-lipoproteins (Hdl) oxidized by gamma radiolysis-generated oxyradicals - effect on their cholesterol effluxing capacity. BBA-Lipid Lipid Met. 1255(1), 23–30 (1995).
MedlineGoogle Scholar
48. Girona J, Laville AE, Sola R, Motta C, Masana L. HDL derived from the different phases of conjugated diene formation reduces membrane fluidity and contributes to a decrease in free cholesterol efflux from human THP-1 macrophages. BBA-Mol. Cell Biol. L. 1633(3), 143–148 (2003).
CASGoogle Scholar
49. Marmillot P, Patel S, Lakshman MR. Reverse cholesterol transport is regulated by varying fatty acyl chain saturation and sphingomyelin content in reconstituted high-density lipoproteins. Metab. Clin. Exp. 56(2), 251–259 (2007).
Medline CASGoogle Scholar
50. Davidson WS, Gillotte KL, Lundkatz S, Johnson WJ, Rothblat GH, Phillips MC. The effect of high-density-lipoprotein phospholipid acyl-chain composition on the efflux of cellular free-cholesterol. J. Biol. Chem. 270(11), 5882–5890 (1995).
Medline CASGoogle Scholar
51. Ramstedt B, Slotte JP. Interaction of cholesterol with sphingomyelins and acyl-chain-matched phosphatidylcholines: a comparative study of the effect of the chain length. Biophys. J. 76(2), 908–915 (1999).
Medline CASGoogle Scholar
52. Ohvo-Rekila H, Ramstedt B, Leppimaki P, Slotte JP. Cholesterol interactions with phospholipids in membranes. Prog. Lipid Res. 41(1), 66–97 (2002).
Medline CASGoogle Scholar
53. Murphy AJ, Woollard KJ, Hoang A et al. High-density lipoprotein reduces the human monocyte inflammatory response. Arterioscl. Throm. Vas. Biol. 28(11), 2071–U2313 (2008).
Medline CASGoogle Scholar
54. Zhu X, Lee JY, Timmins JM et al. Increased cellular free cholesterol in macrophage-specific Abca1 knock-out mice enhances proinflammatory response of macrophages. J. Biol. Chem. 283(34), 22930–22941 (2008).
Medline CASGoogle Scholar
55. Gilchrist M, Thorsson V, Li B et al. Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4. Nature 441(7090), 173–178 (2006).
Medline CASGoogle Scholar
56. Whitmore MM, Iparraguirre A, Kubelka L, Weninger W, Hai T, Williams BRG. Negative regulation of TLR-Signaling pathways by activating transcription factor-3. J. Immunol. 179(6), 3622–3630 (2007).
Medline CASGoogle Scholar
57. Kwon JW, Kwon HK, Shin HJ, Choi YM, Anwar MA, Choi SD. Activating transcription factor 3 represses inflammatory responses by binding to the p65 subunit of NF-kappa B. Sci. Rep. 5, 14470 (2015).
Medline CASGoogle Scholar
58. Poli-De-Figueiredo LF, Garrido AG, Nakagawa NK, Sannomiya P. Experimental models of sepsis and their clinical relevance. Shock 30, 53–59 (2008).
Medline CASGoogle Scholar
59. Lewis AJ, Seymour CW, Rosengart MR. Current murine models of sepsis. Surg. Infect. 17(4), 385–393 (2016).
MedlineGoogle Scholar

Vol. 18, No. 29

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History

Received 8 August 2023

Accepted 1 November 2023

Published online 10 January 2024

Published in print December 2023

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Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/nnm-2023-0222

Author contributions

SY Kim: Design of the experiments; acquisition, analysis, and interpretation of data; draft preparation. J Kang: acquisition, analysis, and interpretation of data. MV Fawaz: acquisition, analysis, and interpretation of data. M Yu: acquisition, analysis, and interpretation of data; editing. Z Xia: acquisition, analysis, and interpretation of data. EE Morin: acquisition, analysis, and interpretation of data. L Mei: acquisition, analysis, and interpretation of data. K Olsen: acquisition, analysis, and interpretation of data. X-A Li: conception. A Schwendeman: conception; supervision; reviewing and editing. Acknowledgments: We would like to thank the histology and hematology services of the In Vivo Animal Core at the University of Michigan for histology data interpretation.

Financial disclosure

This publication was funded by R01GM113832 (X-A Li and A Schwendeman), VA I01BX004639 (X-A Li) and R01GM121796 (X-A Li) as well as support from American Heart Association 20POST3521818 (L Mei), NIH T32 GM007767 (MV Fawaz), NIH T32 GM008353 (EE Morin), NIH T32 HL125242 (MV Fawaz and EE Morin). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

A Schwendeman declares financial interests for board membership, as a paid consultant, for research funding, and as equity holder in EVOQ Therapeutics. The University of Michigan has a financial interest in EVOQ Therapeutics. The authors have no other competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval for all animal experimental investigations. All protocols were approved by the Institutional Animal Care & Use Committee (IACUC) at the University of Michigan, Ann Arbor.

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