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Immunoresolvent Resolvin D1 Maintains the Health of the Ocular Surface

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The Role of Bioactive Lipids in Cancer, Inflammation and Related Diseases

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1161))

Abstract

The present review focuses on the role of one of the D-series resolvins (Rv) RvD1 in the regulation of conjunctival goblet cell secretion and its role in ocular surface health. RvD1 is the most thoroughly studied of the specialized proresolution mediators in the goblet cells. The anterior surface of the eye consists of the cornea (the transparent central area) and the conjunctiva (opaque tissue that surrounds the cornea and lines the eyelids). The secretory mucin MUC5AC produced by the conjunctival goblet cells is protective of the ocular surface and especially helps to maintain clear vision through the cornea. In health, a complex neural reflex stimulates goblet cell secretion to maintain an optimum amount of mucin in the tear film. The specialized pro-resolution mediator, D-series resolvin (RvD1) is present in human tears and induces goblet cell mucin secretion. RvD1 interacts with its receptors ALX/FPR2 and GPR32, activates phospholipases C, D, and A2, as well as the EGFR. This stimulation increases the intracellular [Ca2+] and activates extracellular regulated kinase (ERK) 1/2 to cause mucin secretion into the tear film. This mucin secretion protects the ocular surface from the challenges in the external milieu thus maintaining a healthy interface between the eye and the environment. RvD1 forms a second important mechanism along with activation of a neural reflex pathway to regulate goblet cell mucin secretion and protect the ocular surface in health.

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References

  1. DelMonte DW, Kim T (2011) Anatomy and physiology of the cornea. J Cataract Refract Surg 37(3):588–598

    Article  Google Scholar 

  2. Ramphal R, McNiece MT, Polack FM (1981) Adherence of Pseudomonas aeruginosa to the injured cornea: a step in the pathogenesis of corneal infections. Ann Ophthalmol 13(4):421–425

    CAS  PubMed  Google Scholar 

  3. Streilein JW (2003) Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nat Rev Immunol 3(11):879–889

    Article  CAS  Google Scholar 

  4. Dartt DA (2002) Regulation of mucin and fluid secretion by conjunctival epithelial cells. Prog Retin Eye Res 21(6):555–576

    Article  CAS  Google Scholar 

  5. Gipson IK, Argueso P (2003) Role of mucins in the function of the corneal and conjunctival epithelia. Int Rev Cytol 231:1–49

    Article  CAS  Google Scholar 

  6. Mantelli F, Argueso P (2008) Functions of ocular surface mucins in health and disease. Curr Opin Allergy Clin Immunol 8(5):477–483

    Article  CAS  Google Scholar 

  7. Mauris J, Mantelli F, Woodward AM, Cao Z, Bertozzi CR, Panjwani N et al (2013) Modulation of ocular surface glycocalyx barrier function by a galectin-3 N-terminal deletion mutant and membrane-anchored synthetic glycopolymers. PLoS One 8(8):e72304

    Article  CAS  Google Scholar 

  8. Hodges RR, Dartt DA (2013) Tear film mucins: front line defenders of the ocular surface; comparison with airway and gastrointestinal tract mucins. Exp Eye Res 117:62–78

    Article  CAS  Google Scholar 

  9. Knop E, Knop N (2005) The role of eye-associated lymphoid tissue in corneal immune protection. J Anat 206(3):271–285

    Article  Google Scholar 

  10. Kinoshita S, Ueta M (2010) Innate immunity of the ocular surface. Jpn J Ophthalmol 54(3):194–198

    Article  Google Scholar 

  11. Li D, Hodges RR, Bispo P, Gilmore MS, Gregory-Ksander M, Dartt DA (2017) Neither non-toxigenic Staphylococcus aureus nor commensal S. epidermidi activates NLRP3 inflammasomes in human conjunctival goblet cells. BMJ Open Ophthalmol 2(1):e000101

    Article  Google Scholar 

  12. McGilligan VE, Gregory-Ksander MS, Li D, Moore JE, Hodges RR, Gilmore MS et al (2013) Staphylococcus aureus activates the NLRP3 inflammasome in human and rat conjunctival goblet cells. PLoS One 8(9):e74010

    Article  CAS  Google Scholar 

  13. Barbosa FL, Xiao Y, Bian F, Coursey TG, Ko BY, Clevers H et al (2017) Goblet cells contribute to ocular surface immune tolerance-implications for dry eye disease. Int J Mol Sci 18(5):978

    Article  Google Scholar 

  14. Baudouin C, Rolando M, Benitez Del Castillo JM, Messmer EM, Figueiredo FC, Irkec M et al (2018) Reconsidering the central role of mucins in dry eye and ocular surface diseases. Prog Retin Eye Res. 2018, In Press.

    Google Scholar 

  15. Dartt DA, Masli S (2014) Conjunctival epithelial and goblet cell function in chronic inflammation and ocular allergic inflammation. Curr Opin Allergy Clin Immunol 14(5):464–470

    Article  CAS  Google Scholar 

  16. Dartt DA, Kessler TL, Chung EH, Zieske JD (1996) Vasoactive intestinal peptide-stimulated glycoconjugate secretion from conjunctival goblet cells. Exp Eye Res 63(1):27–34

    Article  CAS  Google Scholar 

  17. Dartt DA, McCarthy DM, Mercer HJ, Kessler TL, Chung EH, Zieske JD (1995) Localization of nerves adjacent to goblet cells in rat conjunctiva. Curr Eye Res 14(11):993–1000

    Article  CAS  Google Scholar 

  18. Kessler TL, Mercer HJ, Zieske JD, McCarthy DM, Dartt DA (1995) Stimulation of goblet cell mucous secretion by activation of nerves in rat conjunctiva. Curr Eye Res 14(11):985–992

    Article  CAS  Google Scholar 

  19. Candia OA, Alvarez LJ (2008) Fluid transport phenomena in ocular epithelia. Prog Retin Eye Res 27(2):197–212

    Article  Google Scholar 

  20. Candia OA, Kong CW, Alvarez LJ (2008) IBMX-elicited inhibition of water permeability in the isolated rabbit conjunctival epithelium. Exp Eye Res 86(3):480–491

    Article  CAS  Google Scholar 

  21. Rios JD, Zoukhri D, Rawe IM, Hodges RR, Zieske JD, Dartt DA (1999) Immunolocalization of muscarinic and VIP receptor subtypes and their role in stimulating goblet cell secretion. Invest Ophthalmol Vis Sci 40(6):1102–1111

    CAS  PubMed  Google Scholar 

  22. Kanno H, Horikawa Y, Hodges RR, Zoukhri D, Shatos MA, Rios JD et al (2003) Cholinergic agonists transactivate EGFR and stimulate MAPK to induce goblet cell secretion. Am J Physiol Cell Physiol 284(4):C988–C998

    Article  CAS  Google Scholar 

  23. Li D, Jiao J, Shatos MA, Hodges RR, Dartt DA (2013) Effect of VIP on intracellular [Ca2+], extracellular regulated kinase 1/2, and secretion in cultured rat conjunctival goblet cells. Invest Ophthalmol Vis Sci 54(4):2872–2884

    Article  CAS  Google Scholar 

  24. Dickson L, Finlayson K (2009) VPAC and PAC receptors: from ligands to function. Pharmacol Ther 121(3):294–316

    Article  CAS  Google Scholar 

  25. Puro DG (2018) Role of ion channels in the functional response of conjunctival goblet cells to dry eye. Am J Physiol Cell Physiol 315(2):C236–CC46

    Article  CAS  Google Scholar 

  26. Serhan CN (2014) Pro-resolving lipid mediators are leads for resolution physiology. Nature 510(7503):92–101

    Article  CAS  Google Scholar 

  27. Williams RN, Bhattacherjee P, Eakins KE (1983) Biosynthesis of lipoxygenase products by ocular tissues. Exp Eye Res 36(3):397–402

    Article  CAS  Google Scholar 

  28. Kulkarni PS, Srinivasan BD (1989) Cyclooxygenase and lipoxygenase pathways in anterior uvea and conjunctiva. Prog Clin Biol Res 312:39–52

    CAS  PubMed  Google Scholar 

  29. Kulkarni PS, Kaufman PL, Srinivasan BD (1987) Eicosapentaenoic acid metabolism in cynomolgus and rhesus conjunctiva and eyelid. J Ocul Pharmacol 3(4):349–356

    Article  CAS  Google Scholar 

  30. Gao Y, Su J, Zhang Y, Chan A, Sin JH, Wu D et al (2018) Dietary DHA amplifies LXA4 circuits in tissues and lymph node PMN and is protective in immune-driven dry eye disease. Mucosal Immunol 11(6):1674–1683

    Article  CAS  Google Scholar 

  31. Gao Y, Min K, Zhang Y, Su J, Greenwood M, Gronert K (2015) Female-specific downregulation of tissue polymorphonuclear neutrophils drives impaired regulatory T cell and amplified effector T cell responses in autoimmune dry eye disease. J Immunol 195(7):3086–3099

    Article  CAS  Google Scholar 

  32. Wei J, Gronert K (2017) The role of pro-resolving lipid mediators in ocular diseases. Mol Asp Med 58:37–43

    Article  CAS  Google Scholar 

  33. Serhan CN, Hamberg M, Samuelsson B (1984) Lipoxins: novel series of biologically active compounds formed from arachidonic acid in human leukocytes. Proc Natl Acad Sci U S A 81(17):5335–5339

    Article  CAS  Google Scholar 

  34. Barden AE, Mas E, Mori TA (2016) n-3 fatty acid supplementation and proresolving mediators of inflammation. Curr Opin Lipidol 27(1):26–32

    Article  CAS  Google Scholar 

  35. Weiss GA, Troxler H, Klinke G, Rogler D, Braegger C, Hersberger M (2013) High levels of anti-inflammatory and pro-resolving lipid mediators lipoxins and resolvins and declining docosahexaenoic acid levels in human milk during the first month of lactation. Lipids Health Dis 12:89

    Article  CAS  Google Scholar 

  36. Arnardottir H, Orr SK, Dalli J, Serhan CN (2016) Human milk proresolving mediators stimulate resolution of acute inflammation. Mucosal Immunol 9(3):757–766

    Article  CAS  Google Scholar 

  37. Mas E, Croft KD, Zahra P, Barden A, Mori TA (2012) Resolvins D1, D2, and other mediators of self-limited resolution of inflammation in human blood following n-3 fatty acid supplementation. Clin Chem 58(10):1476–1484

    Article  CAS  Google Scholar 

  38. Colas RA, Shinohara M, Dalli J, Chiang N, Serhan CN (2014) Identification and signature profiles for pro-resolving and inflammatory lipid mediators in human tissue. Am J Physiol Cell Physiol 307(1):C39–C54

    Article  CAS  Google Scholar 

  39. Zhu M, Wang X, Hjorth E, Colas RA, Schroeder L, Granholm AC et al (2016) Pro-resolving lipid mediators improve neuronal survival and increase Abeta42 phagocytosis. Mol Neurobiol 53(4):2733–2749

    Article  CAS  Google Scholar 

  40. Mukherjee PK, Marcheselli VL, Serhan CN, Bazan NG (2004) Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc Natl Acad Sci U S A 101(22):8491–8496

    Article  CAS  Google Scholar 

  41. English JT, Norris PC, Hodges RR, Dartt DA, Serhan CN (2017) Identification and profiling of specialized pro-resolving mediators in human tears by lipid mediator metabolomics. Prostaglandins Leukot Essent Fat Acids 117:17–27

    Article  CAS  Google Scholar 

  42. Lima-Garcia JF, Dutra RC, da Silva K, Motta EM, Campos MM, Calixto JB (2011) The precursor of resolvin D series and aspirin-triggered resolvin D1 display anti-hyperalgesic properties in adjuvant-induced arthritis in rats. Br J Pharmacol 164(2):278–293

    Article  CAS  Google Scholar 

  43. Walter SD, Gronert K, McClellan AL, Levitt RC, Sarantopoulos KD, Galor A (2016) omega-3 tear film lipids correlate with clinical measures of dry eye. Invest Ophthalmol Vis Sci 57(6):2472–2478

    Article  CAS  Google Scholar 

  44. Masoudi S, Zhao Z, Willcox M (2017) Relation between ocular comfort, arachidonic acid mediators, and histamine. Curr Eye Res 42(6):822–826

    Article  CAS  Google Scholar 

  45. Li D, Hodges RR, Jiao J, Carozza RB, Shatos MA, Chiang N et al (2013) Resolvin D1 and aspirin-triggered resolvin D1 regulate histamine-stimulated conjunctival goblet cell secretion. Mucosal Immunol 6(6):1119–1130

    Article  CAS  Google Scholar 

  46. Dartt DA, Hodges RR, Li D, Shatos MA, Lashkari K, Serhan CN (2011) Conjunctival goblet cell secretion stimulated by leukotrienes is reduced by resolvins D1 and E1 to promote resolution of inflammation. J Immunol 186(7):4455–4466

    Article  CAS  Google Scholar 

  47. Lippestad M, Hodges RR, Utheim TP, Serhan CN, Dartt DA (2017) Resolvin D1 increases mucin secretion in cultured rat conjunctival goblet cells via multiple signaling pathways. Invest Ophthalmol Vis Sci 58(11):4530–4544

    Article  CAS  Google Scholar 

  48. Hodges RR, Li D, Shatos MA, Bair JA, Lippestad M, Serhan CN et al (2017) Lipoxin A4 activates ALX/FPR2 receptor to regulate conjunctival goblet cell secretion. Mucosal Immunol 10(1):46–57

    Article  CAS  Google Scholar 

  49. Hodges RR, Li D, Shatos MA, Serhan CN, Dartt DA (2016) Lipoxin A4 counter-regulates histamine-stimulated glycoconjugate secretion in conjunctival goblet cells. Sci Rep 6:36124

    Article  CAS  Google Scholar 

  50. Zoukhri D, Hodges RR, Sergheraert C, Dartt DA (1998) Protein kinase C isoforms differentially control lacrimal gland functions. Adv Exp Med Biol 438:181–186

    Article  CAS  Google Scholar 

  51. Kaye R, Botten N, Lippestad M, Li D, Hodges RR, Utheim TP et al (2018) Resolvin D1, but not resolvin E1, transactivates the epidermal growth factor receptor to increase intracellular calcium and glycoconjugate secretion in rat and human conjunctival goblet cells. Exp Eye Res 180:53–62

    Article  Google Scholar 

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Acknowledgements

Dr. Dartt is supported by the National Institutes of Health RO1 EY019470 and Dr. Serhan also thanks the NIH for support from 1P01GM095467 (CNS).

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Authors and Affiliations

  1. Schepens Eye Research Institute/Massachusetts Eye and Ear, Boston, MA, USA

    Darlene A. Dartt & Robin R. Hodges

  2. Department of Ophthalmology, Harvard Medical School, Boston, MA, USA

    Darlene A. Dartt & Robin R. Hodges

  3. Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    Charles N. Serhan

  4. Harvard Medical School, Boston, MA, USA

    Charles N. Serhan

Authors
  1. Darlene A. Dartt
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  2. Robin R. Hodges
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  3. Charles N. Serhan
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Corresponding author

Correspondence to Darlene A. Dartt .

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Editors and Affiliations

  1. 431 Chemistry Building, Wayne State University, Detroit, MI, USA

    Kenneth V. Honn

  2. National Institutes of Health, Durham, NC, USA

    Darryl C. Zeldin

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Dartt, D.A., Hodges, R.R., Serhan, C.N. (2019). Immunoresolvent Resolvin D1 Maintains the Health of the Ocular Surface. In: Honn, K., Zeldin, D. (eds) The Role of Bioactive Lipids in Cancer, Inflammation and Related Diseases. Advances in Experimental Medicine and Biology, vol 1161. Springer, Cham. https://doi.org/10.1007/978-3-030-21735-8_3

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