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).