Role of circ_0002590 in Neuroinflammation Via the miR-1184/NLRP1 Axis
                    in Painful Diabetic Neuropathy

Qiao Liu; Mengdie Chen; Xinxiao Cai; Ping Feng

doi:10.1055/a-2676-1452

Experimental and Clinical Endocrinology & Diabetes, Table of Contents

Exp Clin Endocrinol Diabetes 2025; 133(08): 415-424
DOI: 10.1055/a-2676-1452

Article

Role of circ_0002590 in Neuroinflammation Via the miR-1184/NLRP1 Axis in Painful Diabetic Neuropathy

Authors

Qiao Liu

¹Department of Endocrinology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
Mengdie Chen

¹Department of Endocrinology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
Xinxiao Cai

¹Department of Endocrinology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
Ping Feng

¹Department of Endocrinology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China

Abstract

Aim

Painful diabetic neuropathy (PDN), a severe microvascular complication of diabetes, is closely associated with neuroinflammation. This study aimed to investigate the mechanism of circ_0002590 in neuroinflammation associated with PDN.

Methods

The Schwann cells (HEI193) were treated with high glucose (HG, 150 mM) to simulate the diabetic microenvironment. Circ_0002590 expression was silenced using siRNA interference technology and was determined by quantitative real-time reverse transcription polymerase chain reaction. Inflammatory cytokines levels were measured by enzyme-linked immunosorbent assay. The cell counting kit-8 assay was utilized to determine cellular viability. Bioinformatic predictions (TargetScan 8.0 and circRNA Interactome databases) combined with dual-luciferase reporter gene assays and RNA pull-down assays were employed to validate the correlation linking circ_0002590 and miR-1184, as well as between miR-1184 and Nod-like receptor pyrin domain-containing 1 (NLRP1). Rescue assays were performed to confirm the function of the circ_0002590/miR-1184/NLRP1 competing endogenous RNA (ceRNA) network in PDN-associated neuroinflammation.

Results

HG treatment significantly upregulated circ_0002590 expression in HEI193 cells, promoted inflammatory cytokine release, and reduced cell viability. These effects were reversed after circ_0002590 silencing. Circ_0002590 directly interacted with miR-1184 and suppressed miR-1184 expression. miR-1184 targeted and inhibited NLRP1 expression. miR-1184 inhibition or NLRP1 overexpression reversed the anti-inflammatory effects mediated by circ_0002590 silencing.

Conclusions

HG activates the inflammatory response in Schwann cells by inducing circ_0002590 expression, which competitively binds with miR-1184 and thereby alleviates its inhibitory effect on NLRP1.

Keywords

Painful diabetic neuropathy - NLRP1 - circ_0002590 - miR-1184 - Neuroinflammation

Full Text

References

References
1 D’Souza RS, Barman R, Joseph A. et al. Evidence-based treatment of painful diabetic neuropathy: A systematic review. Curr Pain Headache Rep 2022; 26: 583-594
2 Wang Q, Ye Y, Yang L. et al. Painful diabetic neuropathy: The role of ion channels. Biomed Pharmacother 2024; 173: 116417
3 Strand N, Anderson MA, Attanti S. et al. Diabetic neuropathy: Pathophysiology review. Curr Pain Headache Rep 2024; 28: 481-487
4 Zhu J, Hu Z, Luo Y. et al. Diabetic peripheral neuropathy: Pathogenetic mechanisms and treatment. Front Endocrinol (Lausanne) 2023; 14: 1265372
5 M SL, O P. Inflammatory biomarkers as a part of diagnosis in diabetic peripheral neuropathy. J Diabetes Metab Disord 2021; 20: 869-882
6 Baka P, Escolano-Lozano F, Birklein F. Systemic inflammatory biomarkers in painful diabetic neuropathy. J Diabetes Complications 2021; 35: 108017
7 Pop-Busui R, Ang L, Holmes C. et al. Inflammation as a therapeutic target for diabetic neuropathies. Curr Diab Rep 2016; 16: 29
8 Bosch-Queralt M, Fledrich R, Stassart RM. Schwann cell functions in peripheral nerve development and repair. Neurobiol Dis 2023; 176: 105952
9 Majd H, Amin S, Ghazizadeh Z. et al. Deriving Schwann cells from hPSCs enables disease modeling and drug discovery for diabetic peripheral neuropathy. Cell Stem Cell 2023; 30: 632-647 e610
10 Zhang X, Zhao S, Yuan Q. et al. TXNIP, a novel key factor to cause Schwann cell dysfunction in diabetic peripheral neuropathy, under the regulation of PI3K/Akt pathway inhibition-induced DNMT1 and DNMT3a overexpression. Cell Death Dis 2021; 12: 642
11 Naruse K. Schwann cells as crucial players in diabetic neuropathy. Adv Exp Med Biol 2019; 1190: 345-356
12 Zuo Z, Li N, Zhang Q. et al. The role of non-coding RNAs in diabetic retinopathy: Mechanistic insights and therapeutic potential. Mol Neurobiol 2025;
13 Sur S, Pal JK, Shekhar S. et al. Emerging role and clinical applications of circular RNAs in human diseases. Funct Integr Genomics 2025; 25: 77
14 Wang Y, Ding L, Wang R. et al. Circ_0004951 promotes pyroptosis of renal Tubular cells via the NLRP3 inflammasome in diabetic kidney disease. Front Med 2022; 9: 828240
15 Cao H, Xu X, Wang K. et al. Down-regulation of circCOL1A2 suppresses the dysfunction of diabetes-related retinal microvascular endothelial cells via miR-646/FGF7 axis. Curr Eye Res 2022; 47: 1525-1533
16 Yang F, Chen Y, Xue Z. et al. High-throughput sequencing and exploration of the lncRNA-circRNA-miRNA-mRNA network in type 2 diabetes mellitus. Biomed Res Int 2020; 2020: 8162524
17 Zhang HH, Zhang Y, Wang X. et al. Circular RNA profile in diabetic peripheral neuropathy: analysis of coexpression networks of circular RNAs and mRNAs. Epigenomics 2020; 12: 843-857
18 Rykova E, Ershov N, Damarov I. et al. SNPs in 3’UTR miRNA target sequences associated with individual drug susceptibility. Int J Mol Sci 2022; 23: 13725
19 Innocenti T, Bigagli E, Lynch EN. et al. MiRNA-based therapies for the treatment of inflammatory bowel disease: What are we still missing?. Inflamm Bowel Dis 2023; 29: 308-323
20 Liao D, Zhang Y, Li S. et al. miRNAs in neurodegenerative diseases: From target screening to precision therapy. Neurol Sci 2025;
21 Agbu P, Carthew RW. MicroRNA-mediated regulation of glucose and lipid metabolism. Nat Rev Mol Cell Biol 2021; 22: 425-438
22 Morales L, Oliveros JC, Enjuanes L. et al. Contribution of host miRNA-223-3p to SARS-CoV-induced lung inflammatory pathology. mBio 2022; 13: e0313521
23 Bhandari R, Sharma A, Kuhad A. Novel nanotechnological approaches for targeting dorsal root ganglion (DRG) in mitigating diabetic neuropathic pain (DNP). Front Endocrinol 2021; 12: 790747
24 Yang J, Cheng M, Gu B. et al. CircRNA_09505 aggravates inflammation and joint damage in collagen-induced arthritis mice via miR-6089/AKT1/NF-kappaB axis. Cell Death Dis 2020; 11: 833
25 Tong KL, Tan KE, Lim YY. et al. CircRNA-miRNA interactions in atherogenesis. Mol Cell Biochem 2022; 477: 2703-2733
26 Zheng D, Li M, Li G. et al. Circular RNA circ_DROSHA alleviates the neural damage in a cell model of temporal lobe epilepsy through regulating miR-106b-5p/MEF2C axis. Cell Signal 2021; 80: 109901
27 Xia R, Shan Y, Luo S. et al. Circ_0033530 knockdown alleviates lipopolysaccharide-induced acute lung injury model of human lung fibroblasts by mir-1184/Tlr4 axis. Shock 2024; 61: 215-222
28 Liu J, Deng Z, Yu Z. et al. The circRNA circ-Nbea participates in regulating diabetic encephalopathy. Brain Res 2022; 1774: 147702
29 Liu H, Wang X, Wang ZY. et al. Circ_0080425 inhibits cell proliferation and fibrosis in diabetic nephropathy via sponging miR-24-3p and targeting fibroblast growth factor 11. J Cell Physiol 2020; 235: 4520-4529
30 Xu Z, Kombe Kombe AJ, Deng S. et al. NLRP inflammasomes in health and disease. Mol Biomed 2024; 5: 14
31 Costa FRC, Leite JA, Rassi DM. et al. NLRP1 acts as a negative regulator of Th17 cell programming in mice and humans with autoimmune diabetes. Cell Rep 2021; 35: 109176
32 Zhang W, Du M, Jiang Y. et al. miR-103-3p attenuates liver injury with severe acute pancreatitis by inhibiting pyroptosis through miR-103-3p/NLRP1 axis. Acta Histochem 2024; 126: 152211
33 Zhang MJ, Yang L, Li ZY. et al. NLRP1 inflammasome in neurodegenerative disorders: From pathology to therapies. Cytokine Growth Factor Rev 2024; 80: 138-155
34 Li Y, Liu C, Wan XS. et al. NLRP1 deficiency attenuates diabetic retinopathy (DR) in mice through suppressing inflammation response. Biochem Biophys Res Commun 2018; 501: 351-357
35 Rosenberger DC, Blechschmidt V, Timmerman H. et al. Challenges of neuropathic pain: Focus on diabetic neuropathy. J Neural Transm (Vienna) 2020; 127: 589-624
36 Nong W, Bao C, Chen Y. et al. miR-212-3p attenuates neuroinflammation of rats with Alzheimer’s disease via regulating the SP1/BACE1/NLRP3/Caspase-1 signaling pathway. Bosn J Basic Med Sci 2022; 22: 540-552
37 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C(T)) method. Methods 2001; 25: 402-408
38 Dudekula DB, Panda AC, Grammatikakis I. et al. CircInteractome: A web tool for exploring circular RNAs and their interacting proteins and microRNAs. RNA Biol 2016; 13: 34-42
39 McGeary SE, Lin KS, Shi CY. et al. The biochemical basis of microRNA targeting efficacy. Science 2019; 366: eaav1741
40 Petersen EA. Spinal cord stimulation in painful diabetic neuropathy: An overview. Diabetes Res Clin Pract 2023; 206: 110760
41 Jensen TS, Karlsson P, Gylfadottir SS. et al. Painful and non-painful diabetic neuropathy, diagnostic challenges and implications for future management. Brain 2021; 144: 1632-1645
42 Cernea S, Raz I. Management of diabetic neuropathy. Metabolism 2021; 123: 154867
43 Staudt MD, Prabhala T, Sheldon BL. et al. Current strategies for the management of painful diabetic neuropathy. J Diabetes Sci Technol 2022; 16: 341-352
44 Fan W, Pang H, Xie Z. et al. Circular RNAs in diabetes mellitus and its complications. Front Endocrinol 2022; 13: 885650
45 Wang W, Zhang S, Xu L. et al. Involvement of circHIPK3 in the pathogenesis of diabetic cardiomyopathy in mice. Diabetologia 2021; 64: 681-692
46 Qin Y, Xu Y, Peng H. et al. Circ_0123996 promotes the proliferation, inflammation, and fibrosis of mesangial cells by sponging miR-203a-3p to upregulate SOX6 in diabetic nephropathy. J Biochem Mol Toxicol 2022; 36: e23139
47 He L, Liu C, Liu Y. et al. Circular RNA hsa_circ_0084054 promotes the progression of periodontitis with diabetes via the miR-508-3p/PTEN axis. J Periodontal Res 2023; 58: 827-840
48 Li J, Guan R, Pan L. Mechanism of Schwann cells in diabetic peripheral neuropathy: A review. Medicine 2023; 102: e32653
49 Mao S, Zhang S, Zhou S. et al. A Schwann cell-enriched circular RNA circ-Ankib1 regulates Schwann cell proliferation following peripheral nerve injury. FASEB J 2019; 33: 12409-12424
50 Liu G, Zhu D, Feng K. et al. The neurological damage caused by enterovirus 71 infection is associated with hsa_circ_0069335/miR-29b/PMP22 pathway. J Virol 2025; 99: e0084424
51 Huo H, Hu C, Lu Y. et al. Silencing of circCDC14A prevents cerebral ischemia-reperfusion injury via miR-23a-3p/CXCL12 axis. J Biochem Mol Toxicol 2022; 36: e22982
52 Huang L, Guo B, Yan J. et al. CircHSPG2 knockdown attenuates hypoxia-induced apoptosis, inflammation, and oxidative stress in human AC16 cardiomyocytes by regulating the miR-1184/MAP3K2 axis. Cell Stress Chaperones 2023; 28: 177-190
53 Wang D, Han L. Downregulation of miR-1184 serves as a diagnostic biomarker in neonatal sepsis and regulates LPS-induced inflammatory response by inhibiting IL-16 in monocytes. Exp Ther Med 2021; 21: 350
54 Bali KK, Gandla J, Rangel DR. et al. A genome-wide screen reveals microRNAs in peripheral sensory neurons driving painful diabetic neuropathy. Pain 2021; 162: 1334-1351
55 Zhang X, Xia L, Xie A. et al. Low concentration of bupivacaine ameliorates painful diabetic neuropathy by mediating miR-23a/PDE4B axis in microglia. Eur J Pharmacol 2021; 891: 173719
56 Guo B, Xu X, Chi X. et al. Relationship of lncRNA FTX and miR-186-5p levels with diabetic peripheral neuropathy in type 2 diabetes and its bioinformatics analysis. Ir J Med Sci 2024; 193: 2293-2299
57 Cao Y, Zhang H, Lu X. et al. Overexpression of microRNA-9a-5p ameliorates NLRP1 inflammasome-mediated ischemic injury in rats following ischemic stroke. Neuroscience 2020; 444: 106-117
58 Jing G, Wang H, Nan F. et al. Naofucong ameliorates high glucose induced hippocampal neuron injury through suppressing P2X7/NLRP1/caspase-1 pathway. Front Pharmacol 2021; 12: 647116
59 Kong L, Liu Y, Zhang YM. et al. Sarsasapogenin ameliorates diabetes-associated memory impairment and neuroinflammation through down-regulation of PAR-1 receptor. Phytother Res 2021; 35: 3167-3180