Plasmacytoid dendritic cell‐derived secretome ameliorates neuropathic corneal pain

Abstract

Aims/Purpose: Prior work from our group has demonstrated a role for plasmacytoid dendritic cells (pDCs) in corneal nerve homeostasis. Herein, we sought to determine if pDC‐derived secretome could be used for the treatment of neuropathic corneal pain.Methods: The BDCA2‐DTR transgenic mice, in which pDCs can be selectively depleted result in subsequent nerve degeneration, were utilized for ex vivo electrophysiology studies. Animals were treated with pDC secretome drops, beginning 1 day after initial depletion. Electrophysiologic recordings were taken at day 3 post‐depletion analysed. A ciliary nerve ligation model of neuropathic corneal pain (NCP), was used to assess the therapeutic potential of pDC secretome. Spontaneous and evoked pain responses were assessed by palpebral opening measurements and hyperosmolar saline, respectively.Results: There was a significant reduction in cooling threshold following pDC depletion, which was rescued by pDC secretome treatment (26.85 ± 0.65°C vs. 29.52 ± 0.42°C; p < 0.05), restoring the cooling threshold to control levels (29.21 ± 0.51). Furthermore, nerve terminal exhaustion was reduced following pDC depletion and rescued by pDC secretome treatment (0.55 ± 0.08 vs. 1.11 ± 0.10; p < 0.01). Spontaneous pain responses were worse in the vehicle‐treated compared to pDC secretome‐treated group (0.67 ± 0.03 vs. 0.85 ± 0.02; p < 0.001). Similarly, evoked pain responses were worse in the vehicle‐treated compared to pDC secretome‐treated group (30.25 ± 1.50 wipes/30 sec vs. 15.38 ± 1.29; p < 0.0001).Conclusions: Herein, we demonstrate that pDC secretome restores normal functioning of corneal cold receptors. Importantly, in a translational model of NCP, pDC secretome treatment improved both spontaneous and evoked pain responses. Thus, pDC secretome is a viable therapeutic modality for further development and may hold promise in treatment of NCP and other corneal nerve related diseases.Reference1. Jamali A, Kenyon B, Ortiz G, Abou‐Slaybi A, Sendra VG, Harris DL, Hamrah P. Plasmacytoid Dendritic Cells in the Eye. Prog Retin Eye Res 2021; 80: 100877.2. Jamali A, Hu K, Sendra VG, Blanco T, Qazi Y, Zheng L, Turhan A, Hamrah P. Characterization of Resident Corneal Plasmacytoid Dendritic Cells and Their Pivotal Role in Herpes Simplex Keratitis. Cell Rep 2020; 32: 108099.