The Role of Plasma Cell-Free Mitochondrial DNA and Nuclear DNA in Systemic Lupus Erythematosus

Hui-Ting Lee; Chen-Sung Lin; Siao-Cian Pan; Wei-Sheng Chen; Chang-Youh Tsai; Yau-Huei Wei

doi:10.31083/j.fbl2712333

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The Role of Plasma Cell-Free Mitochondrial DNA and Nuclear DNA in Systemic Lupus Erythematosus

Hui-Ting Lee^1,2,†, Chen-Sung Lin^3,4,5,†, Siao-Cian Pan^6,7, Wei-Sheng Chen^4,8, Chang-Youh Tsai^4,8,9,*, Yau-Huei Wei^7,*

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¹ Division of Allergy, Immunology & Rheumatology, Department of Internal Medicine, Mackay Memorial Hospital, 104 Taipei, Taiwan

² Department of Medicine, Mackay Medical College, 252 New Taipei City, Taiwan

³ Division of Thoracic Surgery, Department of Surgery, Taipei Hospital, Ministry of Health and Welfare, 242 New Taipei City, Taiwan

⁴ School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, 112 Taipei, Taiwan

⁵ Center for General Education, Kainan University, 338 Taoyuan City, Taiwan

⁶ Department of Medical Research, National Taiwan University Hospital, 100 Taipei, Taiwan

⁷ Center for Mitochondrial Medicine and Free Radical Research, Changhua Christian Hospital, 500 Changhua City, Taiwan

⁸ Division of Allergy, Immunology & Rheumatology, Department of Medicine, Taipei Veterans General Hospital, 112 Taipei, Taiwan

⁹ Division of Immunology and Rheumatology, Fu-Jen Catholic University Hospital and School of Medicine, Fu-Jen Catholic University, 242 New Taipei City, Taiwan

^*Correspondence: cytsai1240@gmail.com (Chang-Youh Tsai); yhweibabi@gmail.com (Yau-Huei Wei)
^†These authors contributed equally.
Academic Editor: Pietro Gentile

Front. Biosci. (Landmark Ed) 2022, 27(12), 333; https://doi.org/10.31083/j.fbl2712333

Submitted: 26 September 2022 | Revised: 7 December 2022 | Accepted: 8 December 2022 | Published: 27 December 2022

(This article belongs to the Special Issue Cellular response to mitochondrial dysfunction and pathogenic mtDNA mutations)

This is an open access article under the CC BY 4.0 license.

Abstract

Background: The roles of plasma cell-free (pcf) mitochondrial DNA (mtDNA ${}^{\text{pcf}}$ ) and nuclear DNA (nDNA ${}^{\text{pcf}}$ ) in the pathogenesis of systemic lupus erythematosus (SLE) remain unclear. We analyzed the relative copies of mtDNA ${}^{\text{pcf}}$ and nDNA ${}^{\text{pcf}}$ and investigated their association with the levels of plasma 8-hydroxy-2’-deoxyguanosine (8-OHdG), plasma malondialdehyde (MDA) and mRNA of leukocyte C-type lectin domain family 5 member A (CLEC5A) in SLE patients. Methods: A total of 80 SLE patients and 43 healthy controls (HCs) were enrolled. Their plasma samples were subjected to the measurements of mtDNA ${}^{\text{pcf}}$ copies, nDNA ${}^{\text{pcf}}$ copies, 8-OHdG and MDA, respectively. Their leukocytes were analyzed for CLEC5A mRNA expression. Results: SLE patients had higher nDNA ${}^{\text{pcf}}$ copies (2.84 $\pm{}$ 1.99 vs. 2.00 $\pm{}$ 0.88, p = 0.002), lower mtDNA ${}^{\text{pcf}}$ copies (4.81 $\pm{}$ 6.33 vs. 9.83 $\pm{}$ 14.20, p = 0.032), higher plasma 8-OHdG (0.227 $\pm{}$ 0.085 vs. 0.199 $\pm{}$ 0.041 ng/mL, p = 0.016), lower plasma MDA (3.02 $\pm{}$ 2.20 vs. 4.37 $\pm{}$ 2.16 $\mu{}$ M, p = 0.001) and similar leukocyte CLEC5A mRNA expression levels (1.21 $\pm{}$ 1.17 vs. 1.26 $\pm{}$ 1.05, p = 0.870), as compared with those of HCs. Among the HCs, SLE patients with SLE Disease Activity Index (SLEDAI) $\leq$ 8, and SLE patients with SLEDAI $>$ 8, their respective mtDNA ${}^{\text{pcf}}$ copies decreased stepwisely (9.83 $\pm{}$ 14.20 vs. 6.28 $\pm{}$ 7.91 vs. 3.19 $\pm{}$ 3.35, p = 0.054). The nDNA ${}^{\text{pcf}}$ copies of HCs, SLE patients without nephritis, and SLE patients with nephritis were increased stepwisely (2.00 $\pm{}$ 0.88 vs. 2.63 $\pm{}$ 1.74 vs. 3.16 $\pm{}$ 2.34, p = 0.043). Among SLE patients, higher nDNA ${}^{\text{pcf}}$ copies were associated with higher levels of plasma 8-OHdG (p $<$ 0.001) but lower plasma MDA (p = 0.019). Among HCs but not SLE patients, higher nDNA ${}^{\text{pcf}}$ copies (p = 0.013) or lower mtDNA ${}^{\text{pcf}}$ copies (p $<$ 0.001) were related to higher levels of leukocyte CLEC5A mRNA expression. Conclusions: Higher nDNA ${}^{\text{pcf}}$ , lower mtDNA ${}^{\text{pcf}}$ , increased ROS-elicited oxidative DNA damage and dysregulated leukocyte CLEC5A expression might be implicated in the pathogenesis of SLE.

Keywords

plasma cell-free mitochondrial DNA (mtDNA^pcf)

plasma cell-free nuclear DNA (nDNA^pcf)

malondialdehyde (MDA)

8-hydroxy-2'-deoxyguanosine (8-OHdG)

C-type lectin domain family 5 member A (CLEC5A)

systemic lupus erythematosus (SLE)

Funding

MOST 111- 2320-B-371-001/Ministry of Science and Technology

110-CCH-MST- 127/Changhua Christian Hospital

NSC102-2314-B-195-020/National Science Council

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Fig. 1.

Illustration is a proposed mechanism of DNA ${}^{\text{pcf}}$ released from immunocytes/neutrophils under pathogen invasion or stress stimulations, which is involved in the self-antigen presentation in SLE pathogenesis. (a) Lytic NETosis, DNA molecules, including nDNA and mtDNA, as well as other proteins in extruded NET can entangle the pathogens and trigger immune reactions to result in a subsequent lysis of their own cell membrane and the death of invading microbes. (b) Vital NETosis, different from the cell death during lytic NETosis, some immune cells secrete only mtDNA, harboring high immunogenicity, into NET, which enable them to maintain alive even if they become anucleate. (c) Both lytic and vital NETosis could cause the release of DNA into blood circulation and involve the presentation of self-antigen. (d) ROS plays an important regulator in adjusting NETois, and the degrees of ROS-elicited modifications could be reflected by the abundance of 8-OHdG and MDA. (e) CLEC5A can drive human immune response to defend viral infections and is a critical receptor in innate immune system causing NETosis.

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Front. Biosci. (Landmark Ed) Print ISSN 2768-6701 Electronic ISSN 2768-6698