Discussion:
In the last few decades sphingolipids have emerged as vital structural and signaling mediators that regulate varied cellular activities like cell death, proliferation and inflammation(15,16). Ceramide, sphingosine, C1P, S1P are all bioactive lipids and are key modulators in various inflammatory cascades(16,17). Next to cholesteryl esters and waxes, sphingolipids are the major lipid components in the tear and along with phospholipids contribute to the amphiphilic lipids in tear as shown by mass spectrometry analysis which not only comes from the meibum but also from the cellular ocular surface(18). The first link between altered sphingolipids and eye originated from lysosomal storage disease(19). However, recently they have been implicated in dry eye disease, corneal infections, diabetic cornea and age-related macular degeneration(20,21). But their role in conjunctival disorders including VKC needs to be explored.
Our present study revealed altered markers of sphingolipid metabolism in the ocular surface in VKC patients along with differences in the refractory cases. The conjunctival epithelial cells in VKC had significantly reduced levels of ASMA which facilitates ceramide synthesis. However, the ceramide that was estimated in tear namely Cer(d18:1/17:0) showed differential levels in NR and R-VKC. Increased expression of SPHK1 (5-fold) along with increase in SGPL (20-fold) as compared to 4 folds in CERK was noted indicating accumulation of S1P over that of C1P. These findings corroborated with the tear levels of sphingolipids too. Concomitantly, we also found S1PR3 receptor in the conjunctival imprints to be significantly upregulated indicating cellular accumulation of S1P. An altered sphingolipid metabolism was observed at systemic level too with raised S1P and lower C1P in VKC both in NR-VKC and in R-VKC. Both S1P and C1P promote chemotaxis, cell survival and inflammation. A critical balance between these interconvertible metabolites is crucial for normal cell function and any derangement can be detrimental to cells(22,23).
SIP plays an important role in the egress of lymphocytes, while C1P and S1P are involved in eicosanoid synthesis; both prostaglandins and leukotrienes. Besides, they also regulate the cellular arm of inflammatory cascade by promoting neutrophil migration, extravasation, macrophage survival and cytokine production. S1P receptors are present on dendritic cells, eosinophils, Natural Killer cells in addition to mast cells(24). Mast cells exposed to IgE in vitro showed increase in expression of S1PR1 in addition to SIPR3. Activated mast cells release S1P which acts in an autocrine fashion via S1P receptors to enhance mast cell function in addition to causing chemotaxis and degranulation(25).