The research interest of my lab is to study the roles of microRNAs (miRNAs) in the eye and ocular diseases. miRNAs are small, non-coding, regulatory RNAs and constitute a newly recognized level of gene expression regulation. Our long-term goal is to uncover the roles miRNAs in normal development and function of the eye, as well as in ocular diseases so as to identify novel miRNA-based therapeutic targets for the treatment of various ocular diseases.
We reported one of the first miRNA transcriptomes in mouse retina, and identified a conserved paralogous miRNA cluster, the miR-183/96/182 cluster, in the retina and other sensory organs (JBC, 2007). We solved the genomic structure of the miR-183/96/182 cluster gene and demonstrated that inactivation of the miR-183/96/182 cluster gene results in syndromic retinal degeneration with multiple sensory defects (PNAS, 2013; Sci Rep, 2018).
In addition, we discovered that the miR-183/96/182 cluster is also expressed in the cornea, and in the innate immune cells, including neutrophils and macrophages; inactivation of the cluster in mice results in a decreased inflammatory response and reduced severity of Pseudomonas aeruginosa-induced keratitis, providing the first evidence that the miR-183/96/182 cluster plays an important role in innate immune functions and the corneal response to P. aeruginosa infection (IOVS, 2016). Furthermore, with our collaborators, we discovered that that miR-183/96/182 cluster is expressed in Th17 and iNKT cells and promotes Th17 pathogenicity (Immunity, 2016) and plays important roles in iNKT cell development, maturation and effector functions (J Immunol, 2019).
Recently, our new discoveries demonstrated that the corneal resident macrophages are innate IL-17- and IL-10-producing cells; miR-183/96/182 cluster regulates the production of both, as well as the number of steady-state corneal resident macrophages and retinal microglia and the dynamics of innate immune cell infiltration during P. aeruginosa keratitis (ImmunoHorizon. 2020). This is the first example that a miRNA cluster regulates tissue resident macrophage population and their functions in any tissue. This discovery has a profound implication to the roles of miRNAs in innate immunity, since tissue resident macrophages play critical roles in the homeostasis, tissue repair and remodeling and oncogenesis.
On another line of research, we reported the first systemic studies on miRNAs in diabetic retinopathy (DR) and identified a series of miRNAs involved in early DR (IOVS. 2011). This report is recognized to “provide the first insight into the roles of miRNAs in the pathogenesis of DR” by peers in the field. We further showed that miR-146 has a negative feedback regulation on the interleukin 1 receptor (IL-1R)/Toll-like receptor (TLR)-mediated as well as G-protein-coupled receptor (GPCR)-mediated NF-kB activation pathways in RECs through targeting key adaptor molecules of these pathways (IOVS. 2014). Recently our in vivo study in a diabetic rat model showed that intraocular delivery of miR-146 suppressed NF-kB activation pathways, inhibited diabetes-induced upregulation of pro-inflammatory factor and retinal microvascular and neuronal functional defects (IOVS 2017), providing a proof-of-principle evidence that miR-146 is a potential therapeutic target for treatment of DR.
1. Xu S, Coku A, Muraleedharan CK, Harajli A, Mishulin E, Dahabra C, Choi J, Garcia WJ, Webb K, Birch D, Goetz K, Li W. Mutation screening in the miR-183/96/182 cluster in patients with inherited retinal dystrophy. Frontiers Cell and Developmental Biology, 2020 Dec 23; 8:619641. Doi:10.3389/fcell.2020.619641. PMID: 33425925; PMCID: PMC7785829.
2. Coku A, McClellan SA, VanBuren E, Back JB, Hazlett LD, Xu S. The miR-183/96/182 cluster regulates the functions of corneal resident macrophages. ImmunoHorizons 2020 Nov 18;4(11):729-744. doi: 10.4049/immunohorizons.2000091. PMID: 33208381.
3. Zhuang P, Zhang H, Welchko RM, Thompson RC, Xu S, and Turner DL. Combined microRNA and mRNA detection in mammalian retinas by in situ hybridization chain reaction. Sci Rep. 2020 Jan 15;10(1):351. doi: 10.1038/s41598-019-57194-0. PMID: 31942002. DOI:10.1038/s41598-019-57194-0.
4. Wang J, Li G, Wu X, Liu Q, Yin C, Brown S, Xu S, Mi Q, and Zhou L. MiR183-96-182 cluster is involved in invariant NKT cells development, maturation and effector function. J Immunol 2019 Dec 15;203(12):3256-3267. doi: 10.4049/jimmunol.1900695. Epub 2019 Nov 20. PMID: 31748350. DOI:10.4049/jimmunol.1900695.
5. Xu S, Hazlett LD. microRNAs in Ocular Infection. Microorganisms. 2019 Sep 17;7(9). pii: E359. doi: 10.3390/microorganisms7090359. Review. PMID: 31533211. Impact factor: 4.167.
6. Pucella JN, Cols M, Yen W, Xu S, and Chaudhuri J. The B Cell Activation-Induced miR-183 Cluster Plays a Minimal Role in Canonical Primary Humoral Responses. J of Immunology. 2019 Jan 25. pii: ji1800071. doi: 10.4049/jimmunol.1800071. PMID:30683701.
7. Geng R, Furness DN, Muraleedharan CK, Zhang J, Dabdoub A, Lin V, Xu S. The microRNA-183/96/182 Cluster is Essential for Stereociliary Bundle Formation and Function of Cochlear Sensory Hair Cells. Scientific report. 2018 Dec 21;8(1):18022. doi: 10.1038/s41598-018-36894-z. PMID: 30575790. PMCID: PMC6303392.
8. Muraleedharan CK, McClellan, Ekanayaka SA, Francis R, Zmejkoski A, Hazlett LD, and Xu S. The miR-183/96/182 Cluster Regulates Macrophage Functions In Response to Pseudomonas aeruginosa. Journal of Innate Immunity. 2019 Jan 9:1-12. doi: 10.1159/000495472. PMID: 30625496. DOI: 10.1159/000495472.
9. Zhuang P, Muraleedharan CK, Xu S. Intraocular delivery of miR-146 inhibits diabetes-induced retinal functional defects in diabetic rat model. IOVS. 2017; 58:1646-1655. PMID: 28297724.
10. Liu WH, Kang SG, Huang Z, Wu CJ, Jin HY, Maine CJ, Liu Y, Shepherd J, Sabouri-Ghomi M, Gonzalez-Martin A, Xu S, Hoffmann A, Zheng Y, Lu LF, Xiao N, Fu G, Xiao C. A miR-155-Peli1-c-Rel pathway controls the generation and function of T follicular helper cells. J Exp Med. 2016 Aug 1; 213(9): 1901–1919. PMID: 27481129. PMCID: PMC4995083 11. Ichiyama K, Gonzalez-Martin A, Kim BS, Jin HY, Jin W, Xu W, Sabouri-Ghomi M, Xu S, Zheng P, Xiao C, Dong C. The MicroRNA-183-96-182 Cluster Promotes T Helper 17 Cell Pathogenicity by Negatively Regulating Transcription Factor Foxo1 Expression. Immunity 2016;44:1284-98. PMID: 27332731. PMCID: PMC4918454
12. Muraleedharan CK, McClellan SA, Barrett RP, Li C, Montenegro D, Carion T, Berger E, Hazlett LD, and Xu S. Inactivation of the miR-183/96/182 cluster decreases the severity of Pseudomonas aeruginosa-induced keratitis. Invest Ophthalmol Vis Sci. 2016 Apr 1;57(4):1506-17. doi: 10.1167/iovs.16-19134. PMID: 27035623 13. Xu S. microRNAs and inherited retinal dystrophies. Proc Natl Acad Sci U S A. 2015 Jul 9. pii: 201511019. [Epub ahead of print]. PMID:26159420. (Invited commentary) 14. Albers MW, Gilmore GC, Kaye J, Murphy C, Wingfield A, Bennett DA, Boxer AL, Buchman AS, Cruickshanks KJ, Devanand DP, Duffy CJ, Gall CM, Gates GA, Granholm AC, Hensch T, Holtzer R, Hyman BT, Lin FR, McKee AC, Morris JC, Petersen RC, Silbert LC, Struble RG, Trojanowski JQ22, Verghese J, Wilson DA, Xu S, Zhang LI. At the interface of sensory and motor dysfunctions and Alzheimer's disease. Alzheimers Dement. 2015 Jan;11(1):70-98. doi: 10.1016/j.jalz.2014.04.514. Epub 2014 Jul 9. PMID: 25022540
15. Cowan C, Muraleedharan CK, O’Donnell JJ, III, Singh PK, Lum H, Kumar A, and Xu S. microRNA-146 Inhibits Thrombin-induced NF-kB Activation and Subsequent Inflammatory Responses in Human Retinal Endothelial Cells. Invest Ophthalmol Vis Sci. 2014 Jul 1;55(8):4944-51. PMID: 24985472.
16. Lumayag S, Haldin CE, Corbett NJ, Wahlin KJ, Cowan C, Turturro S, Larsen P, Kovacs B, Witmer PD, Valle D, Zack DJ, Nicholson DA, and Xu S. Inactivation of the microRNA-
183/96/182 cluster results in syndromic retinal degeneration. Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):E507-16. doi: 10.1073/pnas.1212655110. Epub 2013 Jan 22.. PMID: 23341629.
17. Kovacs B, Lumayag S, Cowan C, Xu S. microRNAs in early diabetic retinopathy. Invest Ophthalmol Vis Sci. 2011 Jun 21;52(7):4402-9. PMID: 21498619. 18. Li X, Gibson G, Kim JS, Kroin J, Xu S, van Wijnen AJ, Im HJ. MicroRNA-146a is linked to pain-related pathophysiology of osteoarthritis. Gene. 2011 Jul 1;480(1-2):34-41. Epub 2011 Mar 21. PMID:21397669. 19. Xu S. microRNA expression in the eyes and their significance in relation to functions. Prog Retin Eye Res. 2009 Feb;50(2):793-800. Epub 2008 Sep 12. (invited review)
20. Perez SE, Lumayag S, Kovacs B, Mufson EJ and Xu S. (2008) b-Amyloid Deposition and Functional Impairment in the Retina of the APPswe/PS1∆E9 Transgenic Mouse Model of Alzheimer’s Disease. Invest Ophthalmol Vis Sci. 2009 Feb;50(2):793-800.
21. Xu S*, Witmer D, Kovacs B, Lumayag S and Valle D*. (2007). MicroRNA Transcriptome Of Mouse Retina And Functional Study of a Sensory Organ Specific miRNA cluster. J Biol Chem. 282(34):25053-25066. (*: corresponding authors)
22. Liu H, Xu S, Wang Y, Mazerolle C, Thurig S, Coles BLK, Ren J, Taketo MM, van der Kooy D, Wallace VA. (2007). Ciliary margin transdifferentiation from neural retina is controlled by canonical Wnt signaling, Developmental Biology 308(1):54-67.
23. Xu S*, Sunderland ME, Coles BL, Kam A, Holowacz T, Ashery-Padan R, Marquardt T, McInnes RR, van der Kooy D*. (2007). The proliferation and expansion of retinal stem cells require functional Pax6. Dev Biol. 304(2):713-21. (*: corresponding authors) 24. Smukler SR, Runciman SB, Xu S, van der Kooy D. (2006). Embryonic stem cells assume a primitive neural stem cell fate in the absence of extrinsic influences. J Cell Biol. 172(1):79-90.
25. Xu S, Wang Y, Zhao H, Zhang L, Xiong W, Yau KW, Hiel H, Glowatzki E, Ryugo DK, Valle D. (2004). PHR1, a PH Domain-Containing Protein Expressed in Primary Sensory Neurons. Mol Cell Biol. 24:9137-51.
26. Xu S, Ladak R, Swanson DA, Soltyk A, Sun H, Ploder L, Vidgen D, Duncan AM, Garami E, Valle D, McInnes RR. (1999). PHR1 encodes an abundant, pleckstrin homology domain-containing integral membrane protein in the photoreceptor outer segments. J Biol Chem 10;274(50):35676-85.
27. Udar NS*, Xu S*, Bay JO, Dandekar SS, Patel N, Chen X, Liang TY, Uhrhammer N, Klisak I, Shizuya H, Yang H, Samara G, Nelissen J, Sawicki M, Concannon P, Gatti RA. (1999) Physical map of the region surrounding the ataxia-telangiectasia gene on human chromosome 11q22-23. Neuropediatrics 30(4):176-80. (*equal contributions)