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Shaoxue Zeng, Ting Zhang, Yingying Chen, Kaiyu Jin, Xiaohui Fan, Ling Zhu, Mark C Gillies; Jak/STAT signalling mediated glia-neuron interaction following MAPK inhibition. Invest. Ophthalmol. Vis. Sci. 2022;63(7):1176 – A0030.
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© ARVO (1962-2015); The Authors (2016-present)
The dysfunction of Müller cells can induce photoreceptor degeneration. We have previously identified a link between Müller cells and photoreceptors through which inhibition of MAPK signalling in Müller cells upregulated the expression of Interphotoreceptor Retinoid-Binding Protein (IRBP), which is a photoreceptor-specific protein, and prevented photoreceptor degeneration. However, the exact signalling transduction remains unclear. We aim to explore the signalling between Müller cells and photoreceptors in response to stresses.
Retinal tissues from four human eye donors were cultured for 24 hours with PD98059, the ERK1/2 inhibitor, or the same concentration of DMSO as controls. Total RNA was extracted, and its quality was assessed. Next-generation sequencing was performed to explore the transcriptional changes after ERK1/2 inhibition. We then performed QIAGEN Ingenuity Pathway Analysis (IPA) on all the differentially expressed genes (P<0.05) to identify canonical pathways that significantly changed after inhibition of MAPK signalling. We also validated the changes of identified signalling pathways after PD98059 treatment in human retinal explants by Western blot. We further treated the human retinal explants with the specific inhibitors of the identified signalling pathway and evaluated the downstream changes compared with the upstream inhibition of MAPK signalling by Western blot.
IPA analysis found JAK/STAT3 signalling pathway, NF-κB Signaling pathway and Interleukin-6 Signaling pathway were significantly inhibited after the inhibition of MAPK in human retinal explants (P<0.05). Western blotting further validated that the treatment of PD98059 significantly inhibited the phosphorylation levels of STAT3 (the ratio of phosphorylated STAT3 to total STAT3). The treatment of 5,15-DPP, STAT3 specific inhibitor, on human retinal explants significantly increased the expression of neuroprotective IRBP protein by photoreceptors.
Our findings suggest that JAK/STAT3 pathway is involved in the signalling between Müller cells and photoreceptors in response to stresses. The inhibition of JAK/STAT3 pathway activity may have neuroprotective effects on the retina.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.
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