Severe, chronic eye allergy is an understudied, vision-threatening condition. Treatments remain limited. We used a mouse model of severe allergic eye disease (AED) to determine whether topical application of the pro-resolution mediator Resolvin D1 (RvD1) terminates the response. AED was induced by injection of ovalbumin (OVA) followed by topical challenge of OVA daily. RvD1 was applied topically prior to OVA. Clinical symptoms were scored. Eye washes were assayed for MUC5AC. After 7 days, eyes were removed and the number of goblet cells, T helper cell responses and presence of immune cells in draining lymph nodes and conjunctiva determined. Topical RvD1 treatment significantly reduced symptoms of AED. RvD1 did not alter the systemic type 2 immune response in the lymph nodes. AED increased the total amount of goblet cell mucin secretion, but not the number of goblet cells. RvD1 prevented this increase, but did not alter goblet cell number. Absolute numbers of CD4 + T cells, total CD11b + myeloid cells, eosinophils, neutrophils, and monocytes, but not macrophages increased in AED versus RvD1-treated mice. We conclude that topical application of RvD1 reduced the ocular allergic response by local actions in conjunctival immune response and a decrease in goblet cell mucin secretion.
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Gomes, P. J. Trends in prevalence and treatment of ocular allergy. Curr. Opin. Allergy Clin. Immunol. 14, 451–456 (2014).
O’Brien, T. P. Allergic conjunctivitis: an update on diagnosis and management. Curr. Opin. Allergy Clin. Immunol. 13, 543–549 (2013).
Dale, S. B. & Saban, D. R. Linking immune responses with fibrosis in allergic eye disease. Curr. Opin. Allergy Clin. Immunol. 15, 467–475 (2015).
Lee, H. S. et al. Involvement of corneal lymphangiogenesis in a mouse model of allergic eye disease. Invest. Ophthalmol. Vis. Sci. 56, 3140–3148 (2015).
McCulley, J. P., Moore, M. B. & Matoba, A. Y. Mucus fishing syndrome. Ophthalmology 92, 1262–1265 (1985).
Groneberg, D. A., Bielory, L., Fischer, A., Bonini, S. & Wahn, U. Animal models of allergic and inflammatory conjunctivitis. Allergy 58, 1101–1113 (2003).
Lee, H. S., Schlereth, S., Khandelwal, P. & Saban, D. R. Ocular allergy modulation to hi-dose antigen sensitization is a Treg-dependent process. PLoS. ONE 8, e75769 (2013).
Khandelwal, P. et al. Ocular mucosal CD11b+and CD103+mouse dendritic cells under normal conditions and in allergic immune responses. PLoS. ONE 8, e64193 (2013).
Reyes, N. J. & Saban, D. R. T helper subsets in allergic eye disease. Curr. Opin. Allergy Clin. Immunol. 14, 477–484 (2014).
Kari, O. & Saari, K. M. Diagnostics and new developments in the treatment of ocular allergies. Curr. Allergy Asthma Rep. 12, 232–239 (2012).
Ahadome, S. D. et al. Aldehyde dehydrogenase inhibition blocks mucosal fibrosis in human and mouse ocular scarring. JCI Insight 1, e87001 (2016).
Ahadome, S. D. et al. Classical dendritic cells mediate fibrosis directly via the retinoic acid pathway in severe eye allergy. JCI Insight 1, e87012 (2016).
Leonardi, A., Curnow, S. J., Zhan, H. & Calder, V. L. Multiple cytokines in human tear specimens in seasonal and chronic allergic eye disease and in conjunctival fibroblast cultures. Clin. Exp. Allergy 36, 777–784 (2006).
Reyes, N. J., Mathew, R. & Saban, D. R. Induction and characterization of the allergic eye disease mouse model. Methods Mol. Biol. 1799, 49–57 (2018).
Solomon, A. Corneal complications of vernal keratoconjunctivitis. Curr. Opin. Allergy Clin. Immunol. 15, 489–494 (2015).
Garcia-Posadas, L. et al. Interaction of IFN-gamma with cholinergic agonists to modulate rat and human goblet cell function. Mucosal Immunol. 9, 206–217 (2016).
Garcia-Posadas, L., Contreras-Ruiz, L., Soriano-Romani, L., Dartt, D. A. & Diebold, Y. Conjunctival goblet cell function: effect of contact lens wear and cytokines. Eye Contact Lens 42, 83–90 (2016).
Hodges, R. R., Li, D., Shatos, M. A., Serhan, C. N. & Dartt, D. A. Lipoxin A4 counter-regulates histamine-stimulated glycoconjugate secretion in conjunctival goblet cells. Sci. Rep. 6, 36124 (2016).
Li, D. et al. Resolvin D1 and aspirin-triggered resolvin D1 regulate histamine-stimulated conjunctival goblet cell secretion. Mucosal Immunol. 6, 1119–1130 (2013).
Hayashi, D. et al. Role of histamine and its receptor subtypes in stimulation of conjunctival goblet cell secretion. Invest. Ophthalmol. Vis. Sci. 53, 2993–3003 (2012).
Mantelli, F. & Argueso, P. Functions of ocular surface mucins in health and disease. Curr. Opin. Allergy Clin. Immunol. 8, 477–483 (2008).
Dartt, D. A. et al. Conjunctival goblet cell secretion stimulated by leukotrienes is reduced by resolvins D1 and E1 to promote resolution of inflammation. J. Immunol. 186, 4455–4466 (2011).
Contreras-Ruiz, L., Ghosh-Mitra, A., Shatos, M. A., Dartt, D. A. & Masli, S. Modulation of conjunctival goblet cell function by inflammatory cytokines. Mediators. Inflamm. 2013, 636812 (2013).
De Paiva, C. S. et al. Homeostatic control of conjunctival mucosal goblet cells by NKT-derived IL-13. Mucosal Immunol. 4, 397–408 (2011).
Tukler Henriksson, J., Coursey, T. G., Corry, D. B., De Paiva, C. S. & Pflugfelder, S. C. IL-13 stimulates proliferation and expression of mucin and immunomodulatory genes in cultured conjunctival goblet cells. Invest. Ophthalmol. Vis. Sci. 56, 4186–4197 (2015).
Garcia-Posadas, L., Hodges, R. R., Diebold, Y. & Dartt, D. A. Context-dependent regulation of conjunctival function by allergic mediators. Sci. Rep. 8, 12162 (2018).
Serhan, C. N. Discovery of specialized pro-resolving mediators marks the dawn of resolution physiology and pharmacology. Mol. Aspects Med. 58:1–11 (2017).
Serhan, C. N. Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms. FASEB J. 31, 1273–1288 (2017).
Jin, Y. et al. Anti-angiogenesis effect of the novel anti-inflammatory and pro-resolving lipid mediators. Invest. Ophthalmol. Vis. Sci. 50, 4743–4752 (2009).
Hua, J. et al. The resolvin D1 analogue controls maturation of dendritic cells and suppresses alloimmunity in corneal transplantation. Invest. Ophthalmol. Vis. Sci. 55, 5944–5951 (2014).
English, J. T., Norris, P. C., Hodges, R. R., Dartt, D. A. & Serhan, C. N. Identification and profiling of specialized pro-resolving mediators in human tears by lipid mediator metabolomics. Prostaglandins Leukot. Essent. Fatty Acids 117, 17–27 (2017).
Smith, R. E. et al. Secondary allergic T cell responses are regulated by dendritic cell-derived thrombospondin-1 in the setting of allergic eye disease. J. Leukoc. Biol. 100, 371–380 (2016).
Schlereth, S., Lee, H. S., Khandelwal, P. & Saban, D. R. Blocking CCR7 at the ocular surface impairs the pathogenic contribution of dendritic cells in allergic conjunctivitis. Am. J. Pathol. 180, 2351–2360 (2012).
Kunert, K. S., Keane-Myers, A. M., Spurr-Michaud, S., Tisdale, A. S. & Gipson, I. K. Alteration in goblet cell numbers and mucin gene expression in a mouse model of allergic conjunctivitis. Invest. Ophthalmol. Vis. Sci. 42, 2483–2489 (2001).
Merayo-Lloves, J., Calonge, M. & Foster, C. S. Experimental model of allergic conjunctivitis to ragweed in guinea pig. Curr. Eye Res. 14, 487–494 (1995).
Toda, I., Shimazaki, J. & Tsubota, K. Dry eye with only decreased tear break-up time is sometimes associated with allergic conjunctivitis. Ophthalmology 102, 302–309 (1995).
Chiurchiu, V. et al. Proresolving lipid mediators resolvinD1, resolvin D2, and maresin 1 are critical in modulating T cell responses. Sci. Transl. Med 8, 353ra111 (2016).
Chiang, N. & Serhan, C. N. Structural elucidation and physiologic functions of specialized pro-resolving mediators and their receptors. Mol. Aspects Med. 58:114–129 (2017).
Farkouh, A., Frigo, P. & Czejka, M. Systemic side effects of eye drops: a pharmacokinetic perspective. Clin. Ophthalmol. 10, 2433–2441 (2016).
Saban, D. R. The chemokine receptor CCR7 expressed by dendritic cells: a key player in corneal and ocular surface inflammation. Ocul. Surf. 12, 87–99 (2014).
Proud, D. et al. Inflammatory mediator release on conjunctival provocation of allergic subjects with allergen. J. Allergy Clin. Immunol. 85, 896–905 (1990).
Pelikan, Z. Mediator profiles in tears during the conjunctival response induced by allergic reaction in the nasal mucosa. Mol. Vis. 19, 1453–1470 (2013).
Slagle, W. S., Slagle, A. M. & Brough, G. H. Mucus fishing syndrome: case report and new treatment option. Optometry 72, 634–640 (2001).
Vichyanond, P., Pacharn, P., Pleyer, U. & Leonardi, A. Vernal keratoconjunctivitis: a severe allergic eye disease with remodeling changes. Pediatr. Allergy Immunol. 25, 314–322 (2014).
Hodges, R. R. & Dartt, D. A. Tear film mucins: front line defenders of the ocular surface; comparison with airway and gastrointestinal tract mucins. Exp. Eye Res. 117, 62–78 (2013).
Evans, C. M. et al. The polymeric mucin Muc5ac is required for allergic airway hyperreactivity. Nat. Commun. 6, 6281 (2015).
Ono, S. J. & Abelson, M. B. Allergic conjunctivitis: update on pathophysiology and prospects for future treatment. J. Allergy Clin. Immunol. 115, 118–122 (2005).
Takeyama, K. et al. Activation of epidermal growth factor receptors is responsible for mucin synthesis induced by cigarette smoke. Am. J. Physiol. Lung Cell. Mol. Physiol. 280, L165–L172 (2001).
Lee, H. M. et al. Epidermal growth factor receptor signaling mediates regranulation of rat nasal goblet cells. J. Allergy Clin. Immunol. 107, 1046–1050 (2001).
Dartt, D. A., Kessler, T. L., Chung, E. H. & Zieske, J. D. Vasoactive intestinal peptide-stimulated glycoconjugate secretion from conjunctival goblet cells. Exp. Eye Res. 63, 27–34 (1996).
Rios, J. D. et al. Immunolocalization of muscarinic and VIP receptor subtypes and their role in stimulating goblet cell secretion. Invest. Ophthalmol. Vis. Sci. 40, 1102–1111 (1999).
Hodges, R. R. et al. Lipoxin A4 activates ALX/FPR2 receptor to regulate conjunctival goblet cell secretion. Mucosal Immunol. 10, 46–57 (2017).
Norling, L. V., Dalli, J., Flower, R. J., Serhan, C. N. & Perretti, M. Resolvin D1 limits polymorphonuclear leukocyte recruitment to inflammatory loci: receptor-dependent actions. Arterioscler. Thromb. Vasc. Biol. 32, 1970–1978 (2012).
Bielory, B. P., O’Brien, T. P. & Bielory, L. Management of seasonal allergic conjunctivitis: guide to therapy. Acta Ophthalmol. (Copenh) 90, 399–407 (2012).
Sun, Y. P. et al. Resolvin D1 and its aspirin-triggered 17R epimer. Stereochemical assignments, anti-inflammatory properties, and enzymatic inactivation. J. Biol. Chem. 282, 9323–9334 (2007).
Serhan, C. N. et al. Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. J. Exp. Med. 196, 1025–1037 (2002).
Magone, M. T., Chan, C. C., Rizzo, L. V., Kozhich, A. T. & Whitcup, S. M. A novel murine model of allergic conjunctivitis. Clin. Immunol. Immunopathol. 87, 75–84 (1998).
We thank Dr. Tomas Blanco-Mezquita. This study was funded by NIH R01 EY019470 (DAD), R01EY021798 (DRS), P30EY005722 (Duke University), P01GM095467 (CNS), and P30EY003790 (Schepens Eye Research Institute). Supported by NIH RO1 EY019470 (Dartt), P30EY005722 (Saban), R01EY021798 (Saban)
The authors declare no competing interests.