Abstract
Decreased corneal innervation is frequent in patients with Sjögren Syndrome (SS). To investigate the density and morphology of the intraepithelial corneal nerves (ICNs), corneal sensitivity, epithelial cell proliferation, and changes in mRNA expression of genes that are involved in autophagy and axon targeting and extension were assessed using the IL-2 receptor alpha chain (CD25 null) model of SS. ICN density and thickness in male and female wt and CD25 null corneas were assessed at 4, 6, 8, and 10/11 wk of age. Cell proliferation was assessed using ki67. Mechanical corneal sensitivity was measured. Quantitative PCR was performed to quantify expression of beclin 1, LC3, Lamp-1, Lamp-2, CXCL-1, BDNF, NTN1, DCC, Unc5b1, Efna4, Efna5, Rgma, and p21 in corneal epithelial mRNA. A significant reduction in corneal axon density and mechanical sensitivity were observed, which negatively correlate with epithelial cell proliferation. CD25 null mice have increased expression of genes regulating autophagy (beclin-1, LC3, LAMP-1, LAMP-2, CXCL1, and BDNF) and no change was observed in genes that were related to axonal targeting and extension. Decreased anatomic corneal innervation in the CD25 null SS model is accompanied by reduced corneal sensitivity, increased corneal epithelial cell proliferation, and increased expression of genes regulating phagocytosis and autophagy.
Highlights
CD25 is the interleukin-2 receptor α chain (IL2RA)
We find no significant differences in expression in CD25 null corneal epithelium for several mRNAs whose proteins positively mediate axon targeting, including netrin1 and its receptors DCC, Unc5b, and
The primers used were ordered from Bio Rad, unless otherwise specified: Bec1(qMmuCID0005981), LC3, LAMP1, LAMP2, CXCL1, BDNF, NTN1 (Qiagen #QT00128478), DCC (Qiagen #QT00135100), Unc5b (Qiagen #QT00167846), Efna4 (Qiagen #QT00100681), Efna5 (Qiagen #QT00116494), Repulsive guidance molecule a (Rgma) (Qiagen #QT00310583), and GAPDH. quantitative polymerase chain reaction (qPCR) data are normalized against GAPDH
Summary
CD25 is the interleukin-2 receptor α chain (IL2RA). Together with the β (IL2RB) and the γ (IL2RG) chains, it constitutes the high-affinity IL2 receptor (IL2R), which is expressed at high levels on T regulatory (Treg) cells [1,2]. Combining all ages that were assessed results in a negative, significant correlation between axon density and cell proliferation in wt corneas. Combining all ages results in a negative significant correlation between axon density and cell proliferation in CD25 null corneas. While the surgical denervation of all sensory axons reduces corneal epithelial cell proliferation [19,20], the partial denervation that was seen in CD25 null corneas correlates with elevated corneal epithelial cell proliferation
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