Rapamycin Eyedrops Increased CD4+Foxp3+ Cells and Prevented Goblet Cell Loss in the Aged Ocular Surface

Abstract

Dry eye disease (DED), one of the most prevalent conditions among the elderly, is a chronic inflammatory disorder that disrupts tear film stability and causes ocular surface damage. Aged C57BL/6J mice spontaneously develop DED. Rapamycin is a potent immunosuppressant that prolongs the lifespan of several species. Here, we compared the effects of daily instillation of eyedrops containing rapamycin or empty micelles for three months on the aged mice. Tear cytokine/chemokine profile showed a pronounced increase in vascular endothelial cell growth factor-A (VEGF-A) and a trend towards decreased concentration of Interferon gamma (IFN)-γ in rapamycin-treated groups. A significant decrease in inflammatory markers in the lacrimal gland was also evident (IFN-γ, IL-12, CIITA and Ctss); this was accompanied by slightly diminished Unc-51 Like Autophagy Activating Kinase 1 (ULK1) transcripts. In the lacrimal gland and draining lymph nodes, we also observed a significant increase in the CD45+CD4+Foxp3+ cells in the rapamycin-treated mice. More importantly, rapamycin eyedrops increased conjunctival goblet cell density and area compared to the empty micelles. Taken together, evidence from these studies indicates that topical rapamycin has therapeutic efficacy for age-associated ocular surface inflammation and goblet cell loss and opens the venue for new investigations on its role in the aging process of the eye.

Mechanisms of Extraorbital Lacrimal Gland Aging in Mice: An Integrative Analysis of the Temporal Transcriptome

“… 65 , 66 Immunosuppressive interventions, such as topical rapamycin drops, have shown promise in alleviating abnormal ocular surface changes triggered by the lacrimal gland by increasing the number of regulatory T cells in the lacrimal gland. 67 In conclusion, our findings reveal a time-dependent pattern of inflammatory response in the aging lacrimal gland. Striving to maintain a delicate balance between proinflammatory and anti-inflammatory processes during the aging process may potentially forestall or delay functional decline in the lacrimal gland.…”

“…The underlying causes of these SASP-related changes are likely multifaceted, involving factors such as cell proliferation arrest, oncogene activation, and persistent DNA damage. 64 , 67 , 68 However, it is worth noting that SASP can have both positive and negative effects. 62 In the context of the aging lacrimal gland, SASP may promote chronic inflammation and fibrosis, while also maintaining a relatively stable secretory phenotype and regenerative capacity through adaptive and compensatory over-activation of corresponding signaling pathways.…”

“…This finding aligns with previous studies using the mTOR inhibitor rapamycin to reduce the inflammatory response in the aging mouse lacrimal gland and improve clinical symptoms of dry eye. 67 It is important to note that there are direct and indirect interactions between these signaling pathways. For example, the PI3K/Akt axis can suppress the transcriptional activity of FoxO in metabolic organs.…”

Dry eye in Sjögren's syndrome – characteristics and therapy

“…In addition, this treatment resulted in an increase of the density of goblet cells, which are responsible for the secretion of mucin, in the mice conjunctiva. 103 Moreover, the eye drops containing rapamycin decreased the lymphocytic infiltration of the mouse lacrimal glands and corneal fluorescein staining accompanied by elevation of the tear production, which was proved in another animal model using NOD mice with SS. 104 Also, other research group assessed the efficacy of subconjunctival injection of delivery system of rapamycin poly-3-hydroxybutyrate-co-3-hydroxyvalerate microspheres.…”

Age-Related Differences in the Mouse Corneal Epithelial Transcriptome and Their Impact on Corneal Wound Healing

“… 34 , 35 We and others have used aged mice as a model of dry eye disease. As seen in dry eye disease, aged mice have (1) increased corneal permeability, 36 – 38 (2) conjunctival goblet cell loss, 37 , 39 , 40 (3) increased corneal irregularity, 41 (4) increased immune infiltration in the conjunctiva, 42 (5) meibomian gland disease, 43 – 48 (6) an altered tear immunoglobulin profile, 49 (7) altered tear cytokines, 40 , 50 , 51 and (8) increased immune infiltration in the lacrimal gland. 36 , 48 , 50 – 54 Corneal aging produces both structural and functional changes that can affect the ability of the organ to refract light, repair itself, and maintain its barrier function.…”