Myeloid cells protect corneal nerves against sterile injury through negative-feedback regulation of TLR2–IL-6 axis

Lee, Hyun Ju; Kim, Hyeon Ji; Ko, Jung Hwa; Oh, Joo Youn

doi:10.1186/s12974-023-02710-3

Cited by 4 publications

(2 citation statements)

References 60 publications

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“…As reported by a recent study, keratocytes could express and secret IL-6 after sterile corneal injury, which is associated with corneal nerve loss. 51 Accordingly, we found that similar to immune changes, the length, and the branches of corneal mid-stroma nerves were first higher in the 45 D and 75 D groups and returned to the level of the HCs at around 135 days post recovery (see Fig. 3).…”

Section: Discussionsupporting

confidence: 52%

Corneal Stroma Analysis and Related Ocular Manifestations in Recovered COVID-19 Patients

Huang,

Chen,

Chen

et al. 2024

Invest. Ophthalmol. Vis. Sci.

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The purpose of this study was to assess the impact of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) on corneal stroma characteristics, ocular manifestations, and post-recovery refractive surgery outcomes after varying recovery durations. METHODS.Fresh corneal lenticules from patients with post-coronavirus disease 2019 (COVID-19; recovered within 135 days) and healthy controls (HCs) after small incision lenticule extraction (SMILE) surgery were obtained for experimental validation of SARS-CoV-2 susceptibility, morphological changes, and immune response of the corneal stroma. Corneal optical density (CD) was measured using the Pentacam HR. Corneal epithelium thickness (ET) and endothelium parameters were evaluated by wide-field optical coherence tomography (OCT) and non-contact specular microscopy (SP-1P), respectively. All the patients were assessed after SMILE surgery until 3 month of follow-up. RESULTS.The cornea was susceptible to SARS-CoV-2 with the presence of SARS-CoV-2 receptors (CD147 and ACE2) and spike protein remnants (4 out of 58) in post-recovery corneal lenticules. Moreover, SARS-CoV-2 infection triggered immune responses in the corneal stroma, with elevated IL-6 levels observed between 45 and 75 days post-recovery, which were then lower at around day 105. Concurrently, corneal mid-stromal nerve length and branching were initially higher in the 60D to 75D group and returned to control levels by day 135. A similar trend was observed in CD within zones 0 to 2 and 2 to 6 and in the hexagonal cells (HEX) ratio in endothelial cells, whereas ET remained consistent. Notably, these changes did not affect the efficacy, safety, or predictability of post-recovery SMILE surgery.CONCLUSIONS. SARS-CoV-2 induces temporal alterations in corneal stromal morphology and function post-recovery. These findings provided a theoretical basis for corneal health and refractive surgery management in the post-COVID-19 milieu.

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Section: Discussionsupporting

confidence: 52%

Corneal Stroma Analysis and Related Ocular Manifestations in Recovered COVID-19 Patients

Huang,

Chen,

Chen

et al. 2024

Invest. Ophthalmol. Vis. Sci.

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“…This trend was reversed when UCS and UCPRP were administered, indicating that these treatments were able to elevate the expression of Npy following BAK injury and subsequently reduce the expression of the immune-related genes. Such interactions where neuropeptides were observed to facilitate crosstalk between the immune and nervous systems on the ocular surface were documented in recent studies (Wu et al 2022 ; Lee et al 2023 ). However, our findings primarily demonstrated the correlation between inflammatory levels and axonal regeneration in the cornea.…”

Section: Discussionmentioning

confidence: 62%

Cord blood-derived biologics lead to robust axonal regeneration in benzalkonium chloride-injured mouse corneas by modulating the Il-17 pathway and neuropeptide Y

Huang,

Su,

Zhang

et al. 2024

Mol Med

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Background Umbilical cord blood-derived therapeutics, such as serum (UCS) and platelet-rich plasma (UCPRP), are popular treatment options in clinical trials and can potentially be utilized to address a clinically unmet need caused by preservatives, specifically benzalkonium chloride (BAK), present in ophthalmic formulations. As current clinical interventions for secondary injuries caused by BAK are suboptimal, this study will explore the feasibility of utilizing UCS and UCPRP for cornea treatment and investigate the underlying mechanisms associated with this approach. Methods Mice’s corneas were administered BAK to induce damage. UCS and UCPRP were then utilized to attempt to treat the injuries. Ocular tests were performed on the animals to evaluate recovery, while immunostaining, RNA-seq, and subsequent bioinformatics analysis were conducted to investigate the treatment mechanism. Results BAK administration led to widespread inflammatory responses in the cornea. Subsequent treatment with UCS and UCPRP led to the downregulation of immune-related ‘interactions between cytokine receptors’ and ‘IL-17 signaling’ pathways. Although axonal enhancers such as Ngf, Rac2, Robo2, Srgap1, and Rock2 were found to be present in the injured group, robust axonal regeneration was observed only in the UCS and UCPRP treatment groups. Further analysis revealed that, as compared to normal corneas, inflammation was not restored to pre-injury levels post-treatment. Importantly, Neuropeptide Y (Npy) was also involved in regulating immune responses, indicating neuroimmune axis interactions. Conclusions Cord blood-derived therapeutics are feasible options for overcoming the sustained injuries induced by BAK in the cornea. They also have potential applications in areas where axonal regeneration is required.

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Impact of galectin-3 on neurotrophic factor expression by PCR array: potential implications for the human cornea

Woodward,

Argüeso

2024

Front. Cell Dev. Biol.

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The cornea is densely innervated to maintain the integrity of the ocular surface, facilitating functions such as sensation and tear production. Following damage, alterations in the corneal microenvironment can profoundly affect its innervation, potentially impairing healing and sensory perception. One protein frequently upregulated at the ocular surface following tissue damage is galectin-3, but its contribution to corneal nerve regeneration remains unclear. Here, we sought to delineate the role of galectin-3 in regulating the expression of neurotrophic factors by different human cell types. Using a pathway-focused PCR array, we first evaluated the expression of neurotrophic factors in primary cultures of human corneal epithelial cells and fibroblasts. We found that these cell types contributed differently to the expression of these factors, with fibroblasts exhibiting higher levels of nerve growth factor, brain-derived neurotrophic factor, and GDNF compared to epithelial cells. Treatment with exogenous galectin-3 did not significantly affect epithelial cells; however, it did lead to increased synthesis and secretion of IL6, a cytokine known to influence neuronal survival and modulate inflammatory responses, by corneal fibroblasts. Using the human-derived SH-SY5Y cell line as a neuron-like cell model, we also found that galectin-3 stimulated the expression of FOS and LIF, two genes involved in neural differentiation and survival. In summary, these in vitro findings suggest that the presence of galectin-3 in the corneal environment may influence the neuronal response to injury.

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Myeloid cells protect corneal nerves against sterile injury through negative-feedback regulation of TLR2–IL-6 axis

Cited by 4 publications

References 60 publications

Corneal Stroma Analysis and Related Ocular Manifestations in Recovered COVID-19 Patients

Corneal Stroma Analysis and Related Ocular Manifestations in Recovered COVID-19 Patients

Cord blood-derived biologics lead to robust axonal regeneration in benzalkonium chloride-injured mouse corneas by modulating the Il-17 pathway and neuropeptide Y

Impact of galectin-3 on neurotrophic factor expression by PCR array: potential implications for the human cornea

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