miR‑4792 regulates inflammatory responses in <em>Cryptococcus neoformans</em>‑infected microglia

Yao,Guotai; Wang,Xiaoli; Wang,Yan; Hou,Qing; Gao,Rui; Wang,Yilin; Teng,Liang; Lin,Wenting; Wang,Zhongzhi; Jin,Yi; Chen,Jianghan

doi:10.3892/ijmm.2021.5031

miR‑4792 regulates inflammatory responses in Cryptococcus neoformans‑infected microglia

Authors:
- Guotai Yao
- Xiaoli Wang
- Yan Wang
- Qing Hou
- Rui Gao
- Yilin Wang
- Liang Teng
- Wenting Lin
- Zhongzhi Wang
- Yi Jin
- Jianghan Chen
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Affiliations: Department of Dermatology, Changzheng Hospital, Naval Medical University, Shanghai 200003, P.R. China, Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai 200443, P.R. China, Department of Dermatology, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, P.R. China
Published online on: September 9, 2021 https://doi.org/10.3892/ijmm.2021.5031
Article Number: 198

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Abstract

Investigating the factors that influence the inflammatory response of microglial cells is crucial for understanding the pathogenesis of cryptococcal meningitis (CM). MicroRNAs (miRNAs/miRs) play an important role in inducing host defenses and activating the immune response during microbial infection; however, the regulatory mechanisms of miRNAs in cryptococcal meningitis remain poorly defined. In a previous study, the authors assessed the miRNA profiles of THP‑1 (human acute monocytic leukemia cells) cells following Cryptococcus neoformans (C. neoformans) infection. In the present study, it was found that miR‑4792 expression was downregulated in BV2 cells infected with C. neoformans, whilst that of its target gene, epidermal growth factor receptor (EGFR), was upregulated. Infected cells in which miR‑4792 was overexpressed exhibited a decreased EGFR transcript expression, reduced mitogen‑activated protein kinase (MAPK) signaling and a decreased secretion of inflammatory cytokines. In addition, following antifungal treatment in patients with cryptococcal meningitis, the levels of miR‑4792 in the cerebrospinal fluid significantly increased, whilst the expression of EGFR significantly decreased. In addition, receiver operator characteristic analysis revealed miR‑4792 (AUC_ROC=0.75) and EGFR (AUC_ROC=0.79) as potential diagnostic markers in patients with cryptococcal meningitis.

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1	Pappas PG: Cryptococcal infections in non-HIV-infected patients. Trans Am Clin Climatol Assoc. 124:61–79. 2013.PubMed/NCBI
2	Rajasingham R, Smith RM, Park BJ, Jarvis JN, Govender NP, Chiller TM, Denning DW, Loyse A and Boulware DR: Global burden of disease of HIV-associated cryptococcal meningitis: An updated analysis. Lancet Infect Dis. 17:873–881. 2017. View Article : Google Scholar
3	Wu B, Liu H, Huang J, Zhang W and Zhang T: Pulmonary cryptococcosis in non-AIDS patients. Clin Invest Med. 32:E70–E77. 2009. View Article : Google Scholar
4	Kishi K, Homma S, Kurosaki A, Kohno T, Motoi N and Yoshimura K: Clinical features and high-resolution CT findings of pulmonary cryptococcosis in non-AIDS patients. Respir Med. 100:807–812. 2006. View Article : Google Scholar
5	Chang YC, Stins MF, McCaffery MJ, Miller GF, Pare DR, Dam T, Paul-Satyaseela M, Kim KS and Kwon-Chung KJ: Cryptococcal yeast cells invade the central nervous system via transcellular penetration of the blood-brain barrier. Infect Immun. 72:4985–4995. 2004. View Article : Google Scholar
6	Ngamskulrungroj P, Chang Y, Sionov E and Kwon-Chung KJ: The primary target organ of Cryptococcus gattii is different from that of Cryptococcus neoformans in a murine model. mBio. 3:e00103–e00112. 2012. View Article : Google Scholar
7	Chang YC, Bien CM, Lee H, Espenshade PJ and Kwon-Chung KJ: Sre1p, a regulator of oxygen sensing and sterol homeostasis, is required for virulence in Cryptococcus neoformans. Mol Microbiol. 64:614–629. 2007. View Article : Google Scholar
8	Ribes S, Ebert S, Regen T, Agarwal A, Tauber SC, Czesnik D, Spreer A, Bunkowski S, Eiffert H, Hanisch UK, et al: Toll-like receptor stimulation enhances phagocytosis and intracellular killing of nonencapsulated and encapsulated Streptococcus pneumoniae by murine microglia. Infect Immun. 78:865–871. 2010. View Article : Google Scholar
9	Redlich S, Ribes S, Schütze S, Eiffert H and Nau R: Toll-like receptor stimulation increases phagocytosis of Cryptococcus neoformans by microglial cells. J Neuroinflammation. 10:712013. View Article : Google Scholar
10	Gebert L and MacRae IJ: Regulation of microRNA function in animals. Nat Rev Mol Cell Biol. 20:21–37. 2019. View Article : Google Scholar
11	Rupaimoole R and Frank J: Slack MicroRNA therapeutics: Towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 16:203–222. 2017. View Article : Google Scholar
12	Chen H, Jin Y, Chen H, Liao N, Wang Y and Chen J: MicroRNA-mediated inflammatory responses induced by Cryptococcus neoformans are dependent on the NF-κB pathway in human monocytes. Int J Mol Med. 39:1525–1532. 2017. View Article : Google Scholar
13	De Lacorte Singulani J, De Fátima Da Silva J, Gullo FP, Costa MC, Fusco-Almeida AM, Enguita FJ and Mendes-Giannini MJS: Preliminary evaluation of circulating microRNAs as potential biomarkers in paracoccidioidomycosis. Biomed Rep. 6:353–357. 2017. View Article : Google Scholar
14	Kumar M, Ahmad T, Sharma A, Mabalirajan U, Kulshreshtha A, Agrawal A and Ghosh B: Let-7 microRNA-mediated regulation of IL-13 and allergic airway inflammation. J Allergy Clin Immunol. 128:1077–1085. 2011. View Article : Google Scholar
15	Essandoh K, Li Y, Huo J and Fan GC: miRNA-mediated macrophage polarization and its potential role in the regulation of inflammatory response. Shock. 46:122–131. 2016. View Article : Google Scholar
16	Nahid MA, Yao B, Dominguez-Gutierrez PR, Kesavalu L, Satoh M and Chan EK: Regulation of TLR2-mediated tolerance and cross-tolerance through IRAK4 modulation by miR-132 and miR-212. J Immunol. 190:1250–1263. 2013. View Article : Google Scholar
17	Testa U, Pelosi E, Castelli G and Labbaye C: miR-146 and miR-155: two key modulators of immune response and tumor development. Noncoding RNA. 3:22201.
18	Li Y and Chen X: miR-4792 inhibits epithelial-mesenchymal transition and invasion in nasopharyngeal carcinoma by targeting FOXC1. Biochem Biophys Res Commun. 468:863–869. 2015. View Article : Google Scholar
19	Georgieva B, Milev I, Minkov I, Dimitrova I, Bradford AP and Baev V: Characterization of the uterine leiomyoma microR-NAome by deep sequencing. Genomics. 99:275–281. 2012. View Article : Google Scholar
20	Chickooree D, Zhu K, Ram V, Wu HJ, He ZJ and Zhang S: A preliminary microarray assay of the miRNA expression signatures in buccal mucosa of oral submucous fibrosis patients. J Oral Pathol Med. 45:691–697. 2016. View Article : Google Scholar
21	Gabrusiewicz K, Rodriguez B, Wei J, Hashimoto Y, Healy LM, Maiti SN, Thomas G, Zhou S, Wang Q, Elakkad A, et al: Glioblastoma-infiltrated innate immune cells resemble M0 macrophage phenotype. JCI Insight. 1:e858412016. View Article : Google Scholar
22	Li CC, Eaton SA, Young PE, Lee M, Shuttleworth R, Humphreys DT, Grau GE, Combes V, Bebawy M, Gong J, et al: Glioma microvesicles carry selectively packaged coding and non-coding RNAs which alter gene expression in recipient cells. RNA Biol. 10:1333–1344. 2013. View Article : Google Scholar
23	Liu G, Jiang C, Li D, Wang R and Wang W: MiRNA-34a inhibits EGFR-signaling-dependent MMP7 activation in gastric cancer. Tumor Biol. 35:9801–9806. 2014. View Article : Google Scholar
24	Chen S, Zhang Z, Chen L and Zhang J: miRNA 101 3p.1 as an independent diagnostic biomarker aggravates chronic obstructive pulmonary disease via activation of the EGFR/PI3K/AKT signaling pathway. Mol Med Rep. 20:4293–4302. 2019.PubMed/NCBI
25	Ma HP, Kong WX, Li XY, Li W, Zhang Y and Wu Y: miRNA-223 is an anticancer gene in human non-small cell lung cancer through the PI3K/AKT pathway by targeting EGFR. Oncol Rep. 41:1549–1559. 2019.PubMed/NCBI
26	Williamson PR: The relentless march of cryptococcal meningitis. Lancet Infect Dis. 17:790–791. 2017. View Article : Google Scholar
27	Bocchini V, Mazzolla R, Barluzzi R, Blasi E, Sick P and Kettenmann H: An immortalized cell line expresses properties of activated microglial cells. J Neurosci Res. 31:616–621. 1992. View Article : Google Scholar
28	Sheng W, Zong Y, Mohammad A, Ajit D, Cui J, Han D, Hamilton JL, Simonyi A, Sun AY, Gu Z, et al: Pro-inflammatory cytokines and lipopolysaccharide induce changes in cell morphology, and upregulation of ERK1/2, iNOS and sPLA2-IIA expression in astrocytes and microglia. J Neuroinflammation. 8:1212011. View Article : Google Scholar
29	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. View Article : Google Scholar
30	Saag MS, Graybill RJ, Larsen RA, Pappas PG, Perfect JR, Powderly WG, Sobel JD and Dismukes WE: Practice guidelines for the management of cryptococcal disease. Infectious diseases society of America. Clin Infect Dis. 30:710–718. 2000. View Article : Google Scholar
31	Jin Y, Yao G, Wang Y, Teng L, Wang Y, Chen H, Gao R, Lin W, Wang Z and Chen J: MiR-30c-5p mediates inflammatory responses and promotes microglia survival by targeting eIF2α during Cryptococcus neoformans infection. Microb Pathog. 141:1039592020. View Article : Google Scholar
32	Wang WY, Tan MS, Yu JT and Tan L: Role of pro-inflammatory cytokines released from microglia in Alzheimer's disease. Ann Transl Med. 3:1362015.
33	Jin X and Yamashita T: Microglia in central nervous system repair after injury. J Biochem. 159:491–496. 2016. View Article : Google Scholar
34	Kraft AD and Harry GJ: Features of microglia and neuroinflammation relevant to environmental exposure and neurotoxicity. Int J Environ Res Public Health. 8:2980–3018. 2011. View Article : Google Scholar
35	O'Sullivan JB, Ryan KM, Curtin NM, Harkin A and Connor TJ: Noradrenaline reuptake inhibitors limit neuroinflammation in rat cortex following a systemic inflammatory challenge: Implications for depression and neurodegeneration. Int J Neuropsychopharmacol. 12:687–699. 2009. View Article : Google Scholar
36	Loane DJ and Byrnes KR: Role of microglia in neurotrauma. Neurotherapeutics. 7:366–377. 2010. View Article : Google Scholar
37	Bachstetter AD, Xing B, de Almeida L, Dimayuga ER, Watterson DM and Van Eldik LJ: Microglial p38alpha MAPK is a key regulator of proinflammatory cytokine up-regulation induced by toll-like receptor (TLR) ligands or beta-amyloid (Aβ). J Neuroinflammation. 8:792011. View Article : Google Scholar
38	Xu L, Huang Y, Yu X, Yue J, Yang N and Zuo P: The influence of p38 mitogen-activated protein kinase inhibitor on synthesis of inflammatory cytokine tumor necrosis factor alpha in spinal cord of rats with chronic constriction injury. Anesth Analg. 105:1838–1844. 2007. View Article : Google Scholar
39	Kim SH, Smith CJ and Van Eldik LJ: Importance of MAPK pathways for microglial pro-inflammatory cytokine IL-1 beta production. Neurobiol Aging. 25:431–439. 2004. View Article : Google Scholar
40	Qu WS, Tian DS, Guo ZB, Fang J, Zhang Q, Yu ZY, Xie MJ, Zhang HQ, Lü JG and Wang W: Inhibition of EGFR/MAPK signaling reduces microglial inflammatory response and the associated secondary damage in rats after spinal cord injury. J Neuroinflammation. 9:1782012. View Article : Google Scholar
41	Yamauchi T, Ueki K, Tobe K, Tamemoto H, Sekine N, Wada M, Honjo M, Takahashi M, Takahashi T, Hirai H, et al: Growth hormone-induced tyrosine phosphorylation of EGF receptor as an essential element leading to MAP kinase activation and gene expression. Endocr J. 45(Suppl): S27–S31. 1998. View Article : Google Scholar
42	Goel S, Hidalgo M and Perez-Soler R: EGFR inhibitor-mediated apoptosis in solid tumors. J Exp Ther Oncol. 6:305–320. 2007.PubMed/NCBI
43	Pinheiro SB, Sousa ES, Cortez ACA, da Silva Rocha DF, Menescal LSF, Chagas VS, Gómez ASP, Cruz KS, Santos LO, Alves MJ, et al: Cryptococcal meningitis in non-HIV patients in the State of Amazonas, Northern Brazil. J Microbiol. 52:279–288. 2021.
44	Martinez-Nunez RT, Louafi F and Sanchez-Elsner T: The interleukin 13 (IL-13) pathway in human macrophages is modulated by microRNA-155 via direct targeting of interleukin 13 receptor alpha1 (IL13Ralpha1). J Biol Chem. 286:1786–1794. 2011. View Article : Google Scholar
45	Roy S: miRNA in macrophage development and function. Antioxid Redox Signal. 25:795–804. 2016. View Article : Google Scholar
46	Sabiiti W, Robertson E, Beale MA, Johnston SA, Brouwer AE, Loyse A, Jarvis JN, Gilbert AS, Fisher MC, Harrison TS, et al: Efficient phagocytosis and laccase activity affect the outcome of HIV-associated cryptococcosis. J Clin Invest. 124:2000–2008. 2014. View Article : Google Scholar
47	Alanio A, Desnos-Ollivier M and Dromer F: Dynamics of Cryptococcus neoformans-macrophage interactions reveal that fungal background influences outcome during cryptococcal meningoencephalitis in humans. mBio. 2:e00158–e00111. 2011. View Article : Google Scholar
48	Ji RR, Nackley A, Huh Y, Terrando N and Maixner W: Neuroinflammation and central sensitization in chronic and widespread pain. Anesthesiology. 129:343–366. 2018. View Article : Google Scholar
49	Lyman M, Lloyd DG, Ji X, Vizcaychipi MP and Ma D: Neuroinflammation: The role and consequences. Neurosci Res. 79:1–12. 2014. View Article : Google Scholar
50	Kim YK, Na KS, Myint AM and Leonard BE: The role of pro-inflammatory cytokines in neuroinflammation, neurogenesis and the neuroendocrine system in major depression. Prog Neuropsychopharmacol Biol Psychiatry. 64:277–284. 2016. View Article : Google Scholar
51	Henn A, Lund S, Hedtjärn M, Schrattenholz A, Pörzgen P and Leist M: The suitability of BV2 cells as alternative model system for primary microglia cultures or for animal experiments examining brain inflammation. ALTEX. 26:83–94. 2009. View Article : Google Scholar
52	Stansley B, Post J and Hensley K: A comparative review of cell culture systems for the study of microglial biology in Alzheimer's disease. J Neuroinflammation. 9:1152012. View Article : Google Scholar
53	Kofler J and Wiley CA: Microglia: Key innate immune cells of the brain. Toxicol Pathol. 39:103–114. 2011. View Article : Google Scholar
54	Rock RB, Gekker G, Hu S, Sheng WS, Cheeran M, Lokensgard JR and Peterson PK: Role of microglia in central nervous system infections. Clin Microbiol Rev. 17:942–964. 2004. View Article : Google Scholar
55	Barluzzi R, Brozzetti A, Delfino D, Bistoni F and Blasi E: Role of the capsule in microglial cell-Cryptococcus neoformans interaction: Impairment of antifungal activity but not of secretory functions. Med Mycol. 36:189–197. 1998.
56	Neal LM, Xing E, Xu J, Kolbe JL, Osterholzer JJ, Segal BM, Williamson PR and Olszewski MA: CD4⁺T cells orchestrate lethal immune pathology despite fungal clearance during Cryptococcus neoformans meningoencephalitis. mBio. 11:e01415–e01417. 2017.
57	Adami C, Sorci G, Blasi E, Agneletti AL, Bistoni F and Donato R: S100B expression in and effects on microglia. Glia. 33:131–142. 2001. View Article : Google Scholar
58	Song X, Tanaka S, Cox D and Lee SC: Fc gamma receptor signaling in primary human microglia: Differential roles of PI-3K and Ras/ERK MAPK pathways in phagocytosis and chemokine induction. J Leukoc Biol. 75:1147–1155. 2004. View Article : Google Scholar
59	Preissler J, Grosche A, Lede V, Le Duc D, Krügel K, Matyash V, Szulzewsky F, Kallendrusch S, Immig K, Kettenmann H, et al: Altered microglial phagocytosis in GPR34-deficient mice. Glia. 63:206–215. 2015. View Article : Google Scholar
60	Lee SC, Kress Y, Dickson DW and Casadevall A: Human microglia mediate anti-Cryptococcus neoformans activity in the presence of specific antibody. J Neuroimmunol. 62:43–52. 1995. View Article : Google Scholar
61	Lee SC, Kress Y, Zhao ML, Dickson DW and Casadevall A: Cryptococcus neoformans survive and replicate in human microglia. Lab Invest. 73:871–879. 1995.PubMed/NCBI
62	Popovich PG, Guan Z, Wei P, Huitinga I, van Rooijen N and Stokes BT: Depletion of hematogenous macrophages promotes partial hindlimb recovery and neuroanatomical repair after experimental spinal cord injury. Exp Neurol. 158:351–365. 1999. View Article : Google Scholar
63	Stirling DP, Khodarahmi K, Liu J, McPhail LT, McBride CB, Steeves JD, Ramer MS and Tetzlaff W: Minocycline treatment reduces delayed oligodendrocyte death, attenuates axonal dieback, and improves functional outcome after spinal cord injury. J Neurosci. 24:2182–2190. 2004. View Article : Google Scholar
64	Tian DS, Xie MJ, Yu ZY, Zhang Q, Wang YH, Chen B, Chen C and Wang W: Cell cycle inhibition attenuates microglia induced inflammatory response and alleviates neuronal cell death after spinal cord injury in rats. Brain Res. 1135:177–185. 2007. View Article : Google Scholar
65	Gomez-Pinilla F, Knauer DJ and Nieto-Sampedro M: Epidermal growth factor receptor immunoreactivity in rat brain. Development and cellular localization. Brain Res. 438:385–390. 1988. View Article : Google Scholar
66	Erschbamer M, Pernold K and Olson L: Inhibiting epidermal growth factor receptor improves structural, locomotor, sensory, and bladder recovery from experimental spinal cord injury. J Neurosci. 27:6428–6435. 2007. View Article : Google Scholar
67	Jung HW, Son HY, Minh CV, Kim YH and Park YK: Methanol extract of ficus leaf inhibits the production of nitric oxide and proinflammatory cytokines in LPS-stimulated microglia via the MAPK pathway. Phytother Res. 22:1064–1069. 2008. View Article : Google Scholar
68	Correia I, Prieto D, Román E, Wilson D, Hube B, Alonso-Monge R and Pla J: Cooperative role of MAPK pathways in the interaction of Candida albicans with the host epithelium. Microorganisms. 25:482019. View Article : Google Scholar
69	Uenotsuchi T, Takeuchi S, Matsuda T, Urabe K, Koga T, Uchi H, Nakahara T, Fukagawa S, Kawasaki M, Kajiwara H, et al: Differential induction of Th1-prone immunity by human dendritic cells activated with sporothrix schenckii of cutaneous and visceral origins to determine their different virulence. Int Immunol. 18:1637–1646. 2006. View Article : Google Scholar
70	Liu P, Pu J, Zhang J, Chen Z, Wei K and Shi L: Bioinformatic analysis of mir-4792 regulates Radix Tetrastigma hemsleyani flavone to inhibit proliferation, invasion, and induce apoptosis of a549 cells. Onco Targets Ther. 12:1401–1412. 2019. View Article : Google Scholar
71	Lindell DM, Ballinger MN, McDonald RA, Toews GB and Huffnagle GB: Immunologic homeostasis during infection: coexistence of strong pulmonary cell-mediated immunity to secondary Cryptococcus neoformans infection while the primary infection still persists at low levels in the lungs. J Immunol. 177:4652–4661. 2006. View Article : Google Scholar
72	Lindell DM, Ballinger MN, McDonald RA, Toews GB and Huffnagle GB: Diversity of the T-cell response to pulmonary Cryptococcus neoformans infection. Infect Immun. 74:4538–4548. 2006. View Article : Google Scholar
73	Eastman AJ, Osterholzer JJ and Olszewski MA: Role of dendritic cell-pathogen interactions in the immune response to pulmonary cryptococcal infection. Future Microbiol. 10:1837–1857. 2015. View Article : Google Scholar