Downregulation of miR‑1184 serves as a diagnostic biomarker in neonatal sepsis and regulates LPS‑induced inflammatory response by inhibiting IL‑16 in monocytes

Wang,Dan; Han,Lina

doi:10.3892/etm.2021.9781

Downregulation of miR‑1184 serves as a diagnostic biomarker in neonatal sepsis and regulates LPS‑induced inflammatory response by inhibiting IL‑16 in monocytes

Authors:
- Dan Wang
- Lina Han
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Affiliations: Neonatology Department, Weifang People's Hospital, Weifang, Shandong 261041, P.R. China
Published online on: February 11, 2021 https://doi.org/10.3892/etm.2021.9781
Article Number: 350
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Neonatal sepsis (NS) remains a global problem. In the present study, abnormal expression of microRNA‑1184 (miR‑1184) was detected in neonates with NS and it was endeavored to investigate the diagnostic value of miR‑1184, as well as its regulatory role in lipopolysaccharide (LPS)‑induced inflammatory response in vitro. Furthermore, the correlation between interleukin‑16 (IL‑16) and miR‑1184 was investigated to elucidate the pathological mechanisms of NS development. Reverse transcription‑quantitative PCR was used to detect the expression of miR‑1184. Receiver operating characteristic curve analysis was performed to evaluate the diagnostic value of miR‑1184 in NS. Furthermore, a sepsis cell model was established by using LPS‑induced monocytes to explore the effect of miR‑1184 on the inflammatory response. The levels of inflammatory cytokines were determined by ELISA. A luciferase reporter assay was used to investigate the direct targeting interaction between miR‑1184 and IL‑16. The results indicated that the serum levels of miR‑1184 in neonates with sepsis were decreased and miR‑1184 had a high diagnostic value when differentiating NS from respiratory conditions in neonates. In vitro, the expression of miR‑1184 in monocytes was inhibited by LPS and overexpression of miR‑1184 reversed the effect of LPS to stimulate the inflammatory response. IL‑16 was demonstrated to be a target of miR‑1184 and a negative correlation between them was identified in patients with NS. The inflammatory response inhibited by miR‑1184 mimics was enhanced by overexpression of IL‑16 in LPS‑induced monocytes. In conclusion, decreased levels of serum miR‑1184 may be a potential diagnostic biomarker for NS. In addition, miR‑1184 inhibited the LPS‑induced inflammatory response by targeting IL‑16 in monocytes, suggesting that the miR‑1184/IL‑16 axis may be a potential therapeutic target for NS.

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1	Huang H and Tu L: Expression of S100 family proteins in neonatal rats with sepsis and its significance. Int J Clin Exp Pathol. 8:1631–1639. 2015.PubMed/NCBI
2	Shane AL, Sánchez PJ and Stoll BJ: Neonatal sepsis. Lancet. 390:1770–1780. 2017.PubMed/NCBI View Article : Google Scholar
3	Aydemir C, Aydemir H, Kokturk F, Kulah C and Mungan AG: The cut-off levels of procalcitonin and C-reactive protein and the kinetics of mean platelet volume in preterm neonates with sepsis. BMC Pediatr. 18(253)2018.PubMed/NCBI View Article : Google Scholar
4	Giannoni E, Agyeman PKA, Stocker M, Posfay-Barbe KM, Heininger U, Spycher BD, Bernhard-Stirnemann S, Niederer-Loher A, Kahlert CR, Donas A, et al: Swiss Pediatric Sepsis Study: Neonatal sepsis of early onset, and hospital-acquired and community-acquired late onset: a prospective population-based cohort study. J Pediatr. 201:106–114.e4. 2018.PubMed/NCBI View Article : Google Scholar
5	Tzialla C, Manzoni P, Achille C, Bollani L, Stronati M and Borghesi A: New diagnostic possibilities for neonatal sepsis. Am J Perinatol. 35:575–577. 2018.PubMed/NCBI View Article : Google Scholar
6	Wynn JL: Defining neonatal sepsis. Curr Opin Pediatr. 28:135–140. 2016.PubMed/NCBI View Article : Google Scholar
7	Sharma D, Farahbakhsh N, Shastri S and Sharma P: Biomarkers for diagnosis of neonatal sepsis: a literature review. J Matern Fetal Neonatal Med. 31:1646–1659. 2018.PubMed/NCBI View Article : Google Scholar
8	Memar MY, Alizadeh N, Varshochi M and Kafil HS: Immunologic biomarkers for diagnostic of early-onset neonatal sepsis. J Matern Fetal Neonatal Med. 32:143–153. 2019.PubMed/NCBI View Article : Google Scholar
9	Vishnoi A and Rani S: miRNA biogenesis and regulation of diseases: an overview. Methods Mol Biol. 1509:1–10. 2017.PubMed/NCBI View Article : Google Scholar
10	Mishra S, Yadav T and Rani V: Exploring miRNA based approaches in cancer diagnostics and therapeutics. Crit Rev Oncol Hematol. 98:12–23. 2016.PubMed/NCBI View Article : Google Scholar
11	Wang X, Wang X, Liu X, Wang X, Xu J, Hou S, Zhang X and Ding Y: miR-15a/16 are upreuglated in the serum of neonatal sepsis patients and inhibit the LPS-induced inflammatory pathway. Int J Clin Exp Med. 8:5683–5690. 2015.PubMed/NCBI
12	Huang HC, Yu HR, Huang LT, Huang HC, Chen RF, Lin IC, Ou CY, Hsu TY and Yang KD: miRNA-125b regulates TNF-α production in CD14+ neonatal monocytes via post-transcriptional regulation. J Leukoc Biol. 92:171–182. 2012.PubMed/NCBI View Article : Google Scholar
13	Huang HC, Yu HR, Hsu TY, Chen IL, Huang HC, Chang JC and Yang KD: MicroRNA-142-3p and let-7g negatively regulates augmented IL-6 production in neonatal polymorphonuclear leukocytes. Int J Biol Sci. 13:690–700. 2017.PubMed/NCBI View Article : Google Scholar
14	Chen J, Jiang S, Cao Y and Yang Y: Altered miRNAs expression profiles and modulation of immune response genes and proteins during neonatal sepsis. J Clin Immunol. 34:340–348. 2014.PubMed/NCBI View Article : Google Scholar
15	Ahmad SF, Ansari MA, Nadeem A, Bakheet SA, Al-Ayadhi LY and Attia SM: Elevated IL-16 expression is associated with development of immune dysfunction in children with autism. Psychopharmacology (Berl). 236:831–838. 2019.PubMed/NCBI View Article : Google Scholar
16	Mathy NL, Scheuer W, Lanzendörfer M, Honold K, Ambrosius D, Norley S and Kurth R: Interleukin-16 stimulates the expression and production of pro-inflammatory cytokines by human monocytes. Immunology. 100:63–69. 2000.PubMed/NCBI View Article : Google Scholar
17	Zhang F, Yang C, Xing Z, Liu P, Zhang B, Ma X, Huang L and Zhuang L: LncRNA GAS5-mediated miR-1323 promotes tumor progression by targeting TP53INP1 in hepatocellular carcinoma. OncoTargets Ther. 12:4013–4023. 2019.PubMed/NCBI View Article : Google Scholar
18	Smith S, Wu PW, Seo JJ, Fernando T, Jin M, Contreras J, Montano EN, Gabhann JN, Cunningham K, Widaa A, et al: IL-16/miR-125a axis controls neutrophil recruitment in pristane-induced lung inflammation. JCI Insight. 3(120798)2018.PubMed/NCBI View Article : Google Scholar
19	Plotnikov EY, Brezgunova AA, Pevzner IB, Zorova LD, Manskikh VN, Popkov VA, Silachev DN and Zorov DB: Mechanisms of LPS-induced acute kidney injury in neonatal and adult rats. Antioxidants. 7(E105)2018.PubMed/NCBI View Article : Google Scholar
20	Subspecialty Group of Neonatology Pediatric Society Chinese Medical Association; Editorial Board Chinese Journal of Pediatrics. Protocol for diagnosis and treatment of neonatal septicemia. Zhonghua Er Ke Za Zhi. 41:897–899. 2003.PubMed/NCBI(In Chinese).
21	Yu HR, Chen RF, Hong KC, Bong CN, Lee WI, Kuo HC and Yang KD: IL-12-independent Th1 polarization in human mononuclear cells infected with varicella-zoster virus. Eur J Immunol. 35:3664–3672. 2005.PubMed/NCBI View Article : Google Scholar
22	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
23	Rupaimoole R and Slack FJ: MicroRNA therapeutics: Towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 16:203–222. 2017.PubMed/NCBI View Article : Google Scholar
24	Ferrante M and Conti GO: Environment and neurodegenerative diseases: an update on miRNA role. MicroRNA. 6:157–165. 2017.PubMed/NCBI View Article : Google Scholar
25	Correia de Sousa M, Gjorgjieva M, Dolicka D, Sobolewski C and Foti M: Deciphering miRNAs' action through miRNA editing. Int J Mol Sci. 20(E6249)2019.PubMed/NCBI View Article : Google Scholar
26	Jeffries J, Zhou W, Hsu AY and Deng Q: miRNA-223 at the crossroads of inflammation and cancer. Cancer Lett. 451:136–141. 2019.PubMed/NCBI View Article : Google Scholar
27	Yu A, Zhang T, Zhong W, Duan H, Wang S, Ye P, Wang J, Zhong S and Yang Z: miRNA-144 induces microglial autophagy and inflammation following intracerebral hemorrhage. Immunol Lett. 182:18–23. 2017.PubMed/NCBI View Article : Google Scholar
28	Li Y, Ke J, Peng C, Wu F and Song Y: MicroRNA-300/NAMPT regulates inflammatory responses through activation of AMPK/mTOR signaling pathway in neonatal sepsis. Biomed Pharmacother. 108:271–279. 2018.PubMed/NCBI View Article : Google Scholar
29	Cheng Q, Tang L and Wang Y: Regulatory role of miRNA-26a in neonatal sepsis. Exp Ther Med. 16:4836–4842. 2018.PubMed/NCBI View Article : Google Scholar
30	Liu G, Liu W and Guo J: Clinical significance of miR-181a in patients with neonatal sepsis and its regulatory role in the lipopolysaccharide-induced inflammatory response. Exp Ther Med. 19:1977–1983. 2020.PubMed/NCBI View Article : Google Scholar
31	Guo S, Mao X and Liang M: The moderate predictive value of serial serum CRP and PCT levels for the prognosis of hospitalized community-acquired pneumonia. Respir Res. 19(193)2018.PubMed/NCBI View Article : Google Scholar
32	Kim HS, Won S, Lee EK, Chun YH, Yoon JS, Kim HH and Kim JT: Pentraxin 3 as a clinical marker in children with lower respiratory tract infection. Pediatr Pulmonol. 51:42–48. 2016.PubMed/NCBI View Article : Google Scholar
33	To KK, Tong CW, Wu M and Cho WC: MicroRNAs in the prognosis and therapy of colorectal cancer: From bench to bedside. World J Gastroenterol. 24:2949–2973. 2018.PubMed/NCBI View Article : Google Scholar
34	Benz F, Roy S, Trautwein C, Roderburg C and Luedde T: Circulating microRNAs as biomarkers for sepsis. Int J Mol Sci. 17(E78)2016.PubMed/NCBI View Article : Google Scholar
35	Ng PC, Chan KYY, Yuen TP, Sit T, Lam HS, Leung KT, Wong RPO, Chan LCN, Pang YLI, Cheung HM, et al: Plasma miR-1290 is a novel and specific biomarker for early diagnosis of necrotizing enterocolitis-biomarker discovery with prospective cohort evaluation. J Pediatr. 205:83–90.e10. 2019.PubMed/NCBI View Article : Google Scholar
36	van Maldeghem I, Nusman CM and Visser DH: Soluble CD14 subtype (sCD14-ST) as biomarker in neonatal early-onset sepsis and late-onset sepsis: A systematic review and meta-analysis. BMC Immunol. 20(17)2019.PubMed/NCBI View Article : Google Scholar
37	Fatmi A, Rebiahi SA, Chabni N, Zerrouki H, Azzaoui H, Elhabiri Y, Benmansour S, Ibáñez-Cabellos JS, Smahi MC, Aribi M, et al: miRNA-23b as a biomarker of culture-positive neonatal sepsis. Mol Med. 26(94)2020.PubMed/NCBI View Article : Google Scholar : Erratum in: Mol Med 26: 129 2020.
38	Schüller SS, Wisgrill L, Herndl E, Spittler A, Förster-Waldl E, Sadeghi K, Kramer BW and Berger A: Pentoxifylline modulates LPS-induced hyperinflammation in monocytes of preterm infants in vitro. Pediatr Res. 82:215–225. 2017.PubMed/NCBI View Article : Google Scholar
39	Zhang W, Lu F, Xie Y, Lin Y, Zhao T, Tao S, Lai Z, Wei N, Yang R, Shao Y, et al: miR-23b negatively regulates sepsis-induced inflammatory responses by targeting ADAM10 in human THP-1 monocytes. Mediators Inflamm. 2019(5306541)2019.PubMed/NCBI View Article : Google Scholar
40	Roth S, Solbach W and Laskay T: IL-16 and MIF: Messengers beyond neutrophil cell death. Cell Death Dis. 7(e2049)2016.PubMed/NCBI View Article : Google Scholar
41	Sugitharini V, Prema A and Berla Thangam E: Inflammatory mediators of systemic inflammation in neonatal sepsis. Inflamm Res. 62:1025–1034. 2013.PubMed/NCBI View Article : Google Scholar
42	Huang Y, Du KL, Guo PY, Zhao RM, Wang B, Zhao XL and Zhang CQ: IL-16 regulates macrophage polarization as a target gene of mir-145-3p. Mol Immunol. 107:1–9. 2019.PubMed/NCBI View Article : Google Scholar
43	Xia D, Yao R, Zhou P, Wang C, Xia Y and Xu S: LncRNA NEAT1 reversed the hindering effects of miR-495-3p/STAT3 axis and miR-211/PI3K/AKT axis on sepsis-relevant inflammation. Mol Immunol. 117:168–179. 2020.PubMed/NCBI View Article : Google Scholar