MicroRNA-mediated inflammatory responses induced by Cryptococcus neoformans are dependent on the NF-κB pathway in human monocytes

Chen,Hong; Jin,Yi; Chen,Huan; Liao,Ningxin; Wang,Yan; Chen,Jianghan

doi:10.3892/ijmm.2017.2951

MicroRNA-mediated inflammatory responses induced by Cryptococcus neoformans are dependent on the NF-κB pathway in human monocytes

Authors:
- Hong Chen
- Yi Jin
- Huan Chen
- Ningxin Liao
- Yan Wang
- Jianghan Chen
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Affiliations: Department of Dermatology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China, Department of Dermatology, Jinling Hospital, Nanjing 210023, P.R. China
Published online on: April 12, 2017 https://doi.org/10.3892/ijmm.2017.2951
Pages: 1525-1532

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Abstract

Cryptococcosis is a significant invasive fungal infection with noteworthy morbidity and mortality that is usually caused by either Cryptococcus neoformans (C. neoformans) or Cryptococcus gattii (C. gattii). Epidemiological studies have indicated that C. neoformans are more often reported in immunocompromised and immunocompetent patients. It has been well established that the cytokine profile of the host markedly affects the outcome of cryptococcal disease, and the negative regulators of microRNAs(miRs or miRNAs) are critically important for immunomodulation. However, the role of miRNAs and the molecular basis of the inflammatory response induced by C. neoformans in monocytes remain unknown. In this study, we identified 7 differentially expressed miRNAs in THP-1 cells exposed to C. neoformans by Illumina sequencing, and confirmed our findings by RT-qPCR. Furthermore, miR‑146a was selected for further analysis to identify the regulatory mechanisms of inflammation induced by C. neoformans. An examination of the function of miR‑146a in monocytes was performed by overexpressing and inhibiting miR‑146a. In addition, we identified a pattern of induction in response to a variety of microbial components and pro-inflammatory cytokines. Our data suggested that the nuclear factor-κB (NF-κB) pathway was required for the induction of miR‑146a, whereas miR‑146a negatively regulated NF-κB activation by targeting interleukin-1 receptor-associated kinase 1 (IRAK1) and TNF receptor associated factor 6 (TRAF6), then inhibiting NF-κB activation and the release of inflammatory cytokines in monocytes induced by C. neoformans.

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1	Chayakulkeeree M and Perfect JR: Cryptococcosis. Infect Dis Clin North Am. 20:507–544. v–vi. 2006. View Article : Google Scholar : PubMed/NCBI
2	Wu SX, Guo NR, Li XF, Liao WQ, Chen M, Zhang QQ, Li CY, Li RY, Bulmer GS, Li DM, et al: Human pathogenic fungi in China - emerging trends from ongoing national survey for 1986, 1996, and 2006. Mycopathologia. 171:387–393. 2011. View Article : Google Scholar : PubMed/NCBI
3	Hajjeh RA, Conn LA, Stephens DS, Baughman W, Hamill R, Graviss E, Pappas PG, Thomas C, Reingold A, Rothrock G, et al Cryptococcal Active Surveillance Group: Cryptococcosis: Population-based multistate active surveillance and risk factors in human immunodeficiency virus-infected persons. J Infect Dis. 179:449–454. 1999. View Article : Google Scholar : PubMed/NCBI
4	Chen SST, Nimmo G, Speed B, Currie B, Ellis D, Marriott D, Pfeiffer T, Parr D and Byth K: Epidemiology and host- and varietydependent characteristics of infection due to Cryptococcus neoformans in Australia and New Zealand. Australasian Cryptococcal Study Group Clin Infect Dis. 31:92000.
5	Mihara T, Izumikawa K, Kakeya H, Ngamskulrungroj P, Umeyama T, Takazono T, Tashiro M, Nakamura S, Imamura Y, Miyazaki T, et al: Multilocus sequence typing of Cryptococcus neoformans in non-HIV associated cryptococcosis in Nagasaki, Japan. Med Mycol. 51:252–260. 2013. View Article : Google Scholar
6	Saijo T, Chen J, Chen SC, Rosen LB, Yi J, Sorrell TC, Bennett JE, Holland SM, Browne SK and Kwon-Chung KJ: Anti-granulocyte-macrophage colony-stimulating factor autoantibodies are a risk factor for central nervous system infection by Cryptococcus gattii in otherwise immunocompetent patients. MBio. 5:e00912–e00914. 2014. View Article : Google Scholar : PubMed/NCBI
7	Lawrence T and Natoli G: Transcriptional regulation of macrophage polarization: Enabling diversity with identity. Nat Rev Immunol. 11:750–761. 2011. View Article : Google Scholar : PubMed/NCBI
8	Mosser DM and Edwards JP: Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 8:958–969. 2008. View Article : Google Scholar : PubMed/NCBI
9	Martinez FO, Helming L and Gordon S: Alternative activation of macrophages: An immunologic functional perspective. Annu Rev Immunol. 27:451–483. 2009. View Article : Google Scholar
10	Murray PJ and Wynn TA: Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol. 11:723–737. 2011. View Article : Google Scholar : PubMed/NCBI
11	Taylor PR, Martinez-Pomares L, Stacey M, Lin HH, Brown GD and Gordon S: Macrophage receptors and immune recognition. Annu Rev Immunol. 23:901–944. 2005. View Article : Google Scholar : PubMed/NCBI
12	Kawai T and Akira S: The role of pattern-recognition receptors in innate immunity: Update on Toll-like receptors. Nat Immunol. 11:373–384. 2010. View Article : Google Scholar : PubMed/NCBI
13	Kawai T and Akira S: Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity. 34:637–650. 2011. View Article : Google Scholar : PubMed/NCBI
14	Jiménez-Dalmaroni MJ, Radcliffe CM, Harvey DJ, Wormald MR, Verdino P, Ainge GD, Larsen DS, Painter GF, Ulevitch R, Beutler B, et al: Soluble human TLR2 ectodomain binds diacylglycerol from microbial lipopeptides and glycolipids. Innate Immun. 21:175–193. 2015. View Article : Google Scholar :
15	Nakamura K, Miyagi K, Koguchi Y, Kinjo Y, Uezu K, Kinjo T, Akamine M, Fujita J, Kawamura I, Mitsuyama M, et al: Limited contribution of Toll-like receptor 2 and 4 to the host response to a fungal infectious pathogen, Cryptococcus neoformans. FEMS Immunol Med Microbiol. 47:148–154. 2006. View Article : Google Scholar : PubMed/NCBI
16	Yauch LE, Mansour MK, Shoham S, Rottman JB and Levitz SM: Involvement of CD14, toll-like receptors 2 and 4, and MyD88 in the host response to the fungal pathogen Cryptococcus neoformans in vivo. Infect Immun. 72:5373–5382. 2004. View Article : Google Scholar : PubMed/NCBI
17	Akira S, Uematsu S and Takeuchi O: Pathogen recognition and innate immunity. Cell. 124:783–801. 2006. View Article : Google Scholar : PubMed/NCBI
18	Selbach M, Schwanhäusser B, Thierfelder N, Fang Z, Khanin R and Rajewsky N: Widespread changes in protein synthesis induced by microRNAs. Nature. 455:58–63. 2008. View Article : Google Scholar : PubMed/NCBI
19	Friedman RC, Farh KK, Burge CB and Bartel DP: Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 19:92–105. 2009. View Article : Google Scholar :
20	Ebert MS and Sharp PA: Roles for microRNAs in conferring robustness to biological processes. Cell. 149:515–524. 2012. View Article : Google Scholar : PubMed/NCBI
21	Yang C and Wei W: The miRNA expression profile of the uveal melanoma. Sci China Life Sci. 54:351–358. 2011. View Article : Google Scholar : PubMed/NCBI
22	Ambros V: The functions of animal microRNAs. Nature. 431:350–355. 2004. View Article : Google Scholar : PubMed/NCBI
23	Baltimore D, Boldin MP, O'Connell RM, Rao DS and Taganov KD: MicroRNAs: New regulators of immune cell development and function. Nat Immunol. 9:839–845. 2008. View Article : Google Scholar : PubMed/NCBI
24	Lodish HF, Zhou B, Liu G and Chen CZ: Micromanagement of the immune system by microRNAs. Nat Rev Immunol. 8:120–130. 2008. View Article : Google Scholar : PubMed/NCBI
25	Case SR, Martin RJ, Jiang D, Minor MN and Chu HW: MicroRNA-21 inhibits toll-like receptor 2 agonist-induced lung inflammation in mice. Exp Lung Res. 37:500–508. 2011. View Article : Google Scholar : PubMed/NCBI
26	Monk CE, Hutvagner G and Arthur JS: Regulation of miRNA transcription in macrophages in response to Candida albicans. PLoS One. 5:e136692010. View Article : Google Scholar
27	Gantier MP: New perspectives in MicroRNA regulation of innate immunity. J Interferon Cytokine Res. 30:283–289. 2010. View Article : Google Scholar : PubMed/NCBI
28	Taganov KD, Boldin MP, Chang KJ and Baltimore D: NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA. 103:12481–12486. 2006. View Article : Google Scholar : PubMed/NCBI
29	Chen C, Ridzon DA, Broomer AJ, Zhou Z, Lee DH, Nguyen JT, Barbisin M, Xu NL, Mahuvakar VR, Andersen MR, et al: Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res. 33:e1792005. View Article : Google Scholar : PubMed/NCBI
30	Bhaumik D, Scott GK, Schokrpur S, Patil CK, Campisi J and Benz CC: Expression of microRNA-146 suppresses NF-kappaB activity with reduction of metastatic potential in breast cancer cells. Oncogene. 27:5643–5647. 2008. View Article : Google Scholar : PubMed/NCBI
31	Nahid MA, Pauley KM, Satoh M and Chan EK: miR-146a is critical for endotoxin-induced tolerance: IMPLICATION IN INNATE IMMUNITY. J Biol Chem. 284:34590–34599. 2009. View Article : Google Scholar : PubMed/NCBI
32	Hardison SE and Brown GD: C-type lectin receptors orchestrate antifungal immunity. Nat Immunol. 13:817–822. 2012. View Article : Google Scholar : PubMed/NCBI
33	Feriotti C, Loures FV, Frank de Araujo E, da Costa TA and Calich VL: Mannosyl-recognizing receptors induce an M1-like phenotype in macrophages of susceptible mice but an M2-like phenotype in mice resistant to a fungal infection. PLoS One. 8:e548452013. View Article : Google Scholar : PubMed/NCBI
34	Hou J, Wang P, Lin L, Liu X, Ma F, An H, Wang Z and Cao X: MicroRNA-146a feedback inhibits RIG-I-dependent Type I IFN production in macrophages by targeting TRAF6, IRAK1, and IRAK2. J Immunol. 183:2150–2158. 2009. View Article : Google Scholar : PubMed/NCBI
35	Wang P, Hou J, Lin L, Wang C, Liu X, Li D, Ma F, Wang Z and Cao X: Inducible microRNA-155 feedback promotes type I IFN signaling in antiviral innate immunity by targeting suppressor of cytokine signaling 1. J Immunol. 185:6226–6233. 2010. View Article : Google Scholar : PubMed/NCBI
36	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
37	Tili E, Michaille JJ, Cimino A, Costinean S, Dumitru CD, Adair B, Fabbri M, Alder H, Liu CG, Calin GA, et al: Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock. J Immunol. 179:5082–5089. 2007. View Article : Google Scholar : PubMed/NCBI
38	Jazdzewski K, Liyanarachchi S, Swierniak M, Pachucki J, Ringel MD, Jarzab B and de la Chapelle A: Polymorphic mature microRNAs from passenger strand of pre-miR-146a contribute to thyroid cancer. Proc Natl Acad Sci USA. 106:1502–1505. 2009. View Article : Google Scholar : PubMed/NCBI
39	Pauley KM, Satoh M, Chan AL, Bubb MR, Reeves WH and Chan EK: Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Res Ther. 10:R1012008. View Article : Google Scholar : PubMed/NCBI
40	Yamasaki K, Nakasa T, Miyaki S, Ishikawa M, Deie M, Adachi N, Yasunaga Y, Asahara H and Ochi M: Expression of MicroRNA-146a in osteoarthritis cartilage. Arthritis Rheum. 60:1035–1041. 2009. View Article : Google Scholar : PubMed/NCBI
41	Tang Y, Luo X, Cui H, Ni X, Yuan M, Guo Y, Huang X, Zhou H, de Vries N, Tak PP, et al: MicroRNA-146A contributes to abnormal activation of the type I interferon pathway in human lupus by targeting the key signaling proteins. Arthritis Rheum. 60:1065–1075. 2009. View Article : Google Scholar : PubMed/NCBI
42	Wu S, He L, Li Y, Wang T, Feng L, Jiang L, Zhang P and Huang X: miR-146a facilitates replication of dengue virus by dampening interferon induction by targeting TRAF6. J Infect. 67:329–341. 2013. View Article : Google Scholar : PubMed/NCBI
43	Takeda K and Akira S: TLR signaling pathways. Semin Immunol. 16:3–9. 2004. View Article : Google Scholar : PubMed/NCBI
44	Seki E and Brenner DA: Toll-like receptors and adaptor molecules in liver disease: Update. Hepatology. 48:322–335. 2008. View Article : Google Scholar : PubMed/NCBI
45	Zhao JL, Rao DS, Boldin MP, Taganov KD, O'Connell RM and Baltimore D: NF-kappaB dysregulation in microRNA-146a-deficient mice drives the development of myeloid malignancies. Proc Natl Acad Sci USA. 108:9184–9189. 2011. View Article : Google Scholar : PubMed/NCBI
46	Yang K, He YS, Wang XQ, Lu L, Chen QJ, Liu J, Sun Z and Shen WF: MiR-146a inhibits oxidized low-density lipoprotein-induced lipid accumulation and inflammatory response via targeting toll-like receptor 4. FEBS Lett. 585:854–860. 2011. View Article : Google Scholar : PubMed/NCBI
47	Mei J, Bachoo R and Zhang CL: MicroRNA-146a inhibits glioma development by targeting Notch1. Mol Cell Biol. 31:3584–3592. 2011. View Article : Google Scholar : PubMed/NCBI
48	Takeda K: Evolution and integration of innate immune recognition systems: The Toll-like receptors. J Endotoxin Res. 11:51–55. 2005. View Article : Google Scholar : PubMed/NCBI
49	Li L, Cousart S, Hu J and McCall CE: Characterization of interleukin-1 receptor-associated kinase in normal and endotoxin-tolerant cells. J Biol Chem. 275:23340–23345. 2000. View Article : Google Scholar : PubMed/NCBI
50	Boone DL, Turer EE, Lee EG, Ahmad RC, Wheeler MT, Tsui C, Hurley P, Chien M, Chai S, Hitotsumatsu O, et al: The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat Immunol. 5:1052–1060. 2004. View Article : Google Scholar : PubMed/NCBI
51	Nahid MA, Satoh M and Chan EK: Mechanistic role of microRNA-146a in endotoxin-induced differential cross-regulation of TLR signaling. J Immunol. 186:1723–1734. 2011. View Article : Google Scholar