Subconjunctival Injection of Regulatory T Cells Potentiates Corneal Healing Via Orchestrating Inflammation and Tissue Repair After Acute Alkali Burn

Abstract

Purpose This study aimed to investigate the therapeutic effects and underlying mechanisms of locally delivered regulatory T cells (Tregs) on acute corneal wound healing after alkali burn. Methods After corneal alkali burn, the mice were injected subconjunctivally with regulatory T cells (Tregs) isolated from syngeneic mice. The wound healing process was monitored by clinical manifestation, flow cytometry, and enzyme-linked immunosorbent assay (ELISA). As amphiregulin (Areg) was significantly upregulated, its reparative function in injured corneas was suggested. The hypothesis was further verified via loss- and gain-of-function experiments by administrating the antibody of Areg (anti-Areg) and recombinant Areg (rmAreg). Results Subconjunctivally injected Tregs rapidly migrated to injured corneas. The mice treated with Tregs showed prominently reduced corneal opacity, alleviated edema, and faster re-epithelialization compared with the control group. Mechanistically, Treg treatment led to suppressed infiltration of inflammatory cells, along with improved proliferation and inhibited apoptosis of corneal epithelial cells. Tregs expressed upregulated functional markers, including Areg. Expectantly, the levels of Areg in corneas were dramatically higher in the Treg injection group, in line with better corneal restoration. Additional experiments showed that the administration of anti-Areg blunted the reparative effect of Tregs, while exogenous Areg enhanced it. Treg-treated corneas also exhibited less neovascularization and fibrosis at a later reconstruction stage of corneal repair. Conclusions The findings showed that the subconjunctival injection of Tregs effectively promoted corneal wound healing by inhibiting excessive inflammation and enhancing epithelial regeneration, with an indispensable reparative role of Areg. Subsequent complications of corneal vascularization and fibrosis were therefore reduced.

The advanced glycation end-products (AGEs)/ROS/NLRP3 inflammasome axis contributes to delayed diabetic corneal wound healing and nerve regeneration

“…Wound healing is an important and complicated process for maintaining corneal homeostasis and transparency, involving in various cell types, such as corneal epithelial cells, stem cells, neurons and immune cells [56,57]. Although we have demonstrated the different roles of NLRP3 inflammasome in physiological and diabetic corneal wound healing, there are still several limitations in need of resolution.…”

Relationship between dry eye and expressions of CXCR3 and CCR5 after ocular acid burn

“…And severe periorbital edema or inflammation of the trabecular meshwork after a burn can lead to high intraocular pressure [ 11 ]. The inflammatory cascade after chemical ocular injury is mainly the activation of pro-inflammatory signaling pathway (NF-κB/ NLRp3-Caspase1-IL-1 β), followed by a series of downstream inflammatory events [ 14 ]. First, transcription factor—nuclear factor (NF-κB) and inflammatory body NLRP3 are increased, which activate macrophages and cause autoimmune responses.…”

Regulatory T Cells: Liquid and Living Precision Medicine for the Future of VCA

“…6,108,109 The local injection of Treg has already been investigated in several studies with promising results, including the inhibition of inflammation and orchestration of tissue repair. 110,111 Yet, this approach remains to be translated to the field of VCA. 112 It is important to note that the topical immunomodulatory drugs currently in clinical use can impact the Treg population.…”