Absence of Therapeutic Benefit of the Anti-Inflammatory Protein TSG-6 for Corneal Alkali Injury in a Rat Model

Choi, Hosoon; Phillips, Casie; Oh, Joo Youn; Potts, Luke B.; Reger, Roxanne L.; Prockop, Darwin J.; Fulcher, Samuel

doi:10.1080/02713683.2019.1597893

Cited by 6 publications

(4 citation statements)

References 34 publications

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“…In support of this hypothesis, a recent study suggested that acute administration of TSG-6 showed remarkable improvement in memory after TBI [42]. However, it must be noted that TSG-6 was effective only when administered during the initial and mild phase of an inflammatory reaction in a corneal mechanical injury model [20] with no therapeutic benefit in a corneal alkali injury model [51]. This suggests that TSG-6 alone may not likely to prevent ongoing tissue degeneration in TBI, while on the other hand, the powerful antioxidant and immunomodulatory proteins in addition to TSG-6 in ASC-CCM will not only suppress ongoing inflammation but also aid in the regeneration.…”

Section: Discussionmentioning

confidence: 99%

TSG-6 in conditioned media from adipose mesenchymal stem cells protects against visual deficits in mild traumatic brain injury model through neurovascular modulation

et al. 2019

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BackgroundRetinal inflammation affecting the neurovascular unit may play a role in the development of visual deficits following mild traumatic brain injury (mTBI). We have shown that concentrated conditioned media from adipose tissue-derived mesenchymal stem cells (ASC-CCM) can limit retinal damage from blast injury and improve visual function. In this study, we addressed the hypothesis that TNFα-stimulated gene-6 (TSG-6), an anti-inflammatory protein released by mesenchymal cells, mediates the observed therapeutic potential of ASCs via neurovascular modulation.MethodsAbout 12-week-old C57Bl/6 mice were subjected to 50-psi air pulse on the left side of the head overlying the forebrain resulting in an mTBI. Age-matched sham blast mice served as control. About 1 μl of ASC-CCM (siControl-ASC-CCM) or TSG-6 knockdown ASC-CCM (siTSG-6-ASC-CCM) was delivered intravitreally into both eyes. One month following injection, the ocular function was assessed followed by molecular and immunohistological analysis. In vitro, mouse microglial cells were used to evaluate the anti-inflammatory effect of ASC-CCM. Efficacy of ASC-CCM in normalizing retinal vascular permeability was assessed using trans-endothelial resistance (TER) and VE-cadherin expression in the presence of TNFα (1 ng/ml).ResultsWe show that intravitreal injection of ASC-CCM (siControl-ASC-CCM) but not the TSG-6 knockdown ASC-CCM (siTSG-6-ASC-CCM) mitigates the loss of visual acuity and contrast sensitivity, retinal expression of genes associated with microglial and endothelial activation, and retinal GFAP immunoreactivity at 4 weeks after blast injury. In vitro, siControl-ASC-CCM but not the siTSG-6-ASC-CCM not only suppressed microglial activation and STAT3 phosphorylation but also protected against TNFα-induced endothelial permeability as measured by transendothelial electrical resistance and decreased STAT3 phosphorylation.ConclusionsOur findings suggest that ASCs respond to an inflammatory milieu by secreting higher levels of TSG-6 that mediates the resolution of the inflammatory cascade on multiple cell types and correlates with the therapeutic potency of the ASC-CCM. These results expand our understanding of innate mesenchymal cell function and confirm the importance of considering methods to increase the production of key analytes such as TSG-6 if mesenchymal stem cell secretome-derived biologics are to be developed as a treatment solution against the traumatic effects of blast injuries and other neurovascular inflammatory conditions of the retina.

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Section: Discussionmentioning

confidence: 99%

TSG-6 in conditioned media from adipose mesenchymal stem cells protects against visual deficits in mild traumatic brain injury model through neurovascular modulation

et al. 2019

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“…Successful wound repair requires efficient resolution of aggravated inflammation after injury because the dysregulation of alkali-elicited immune responses have the risk of inducing collateral tissue damage. [50][51][52] After Treg treatment, the prognosis of corneal alkali burns improved with an apparent reduction of fibrosis and improvement in corneal transparency. It was speculated that reduction of corneal scar and neovascularization may be attributed to the efficient resolution of local inflammation by Tregs.…”

Section: Discussionmentioning

confidence: 99%

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

Yan

Chen

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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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.

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“…Corneal stromal opacity was evaluated based on the opacification scoring system (score 0: no opacity; score 1: slight superficial opacity, iris details visible; score 2: moderate stromal opacity, pupillary margin visible, iris details not visible; score 3: significant stromal opacity, pupillary margin not visible; score 4: completely opaque, pupil and anterior chamber not visible) [ 46 ].…”

Section: Methodsmentioning

confidence: 99%

Interferon-γ elicits the ocular surface pathology mimicking dry eye through direct modulation of resident corneal cells

Kim

Ryu

et al. 2023

Cell Death Discov.

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Despite accumulating evidence indicating a key role of interferon-γ (IFN-γ)-producing immune cells in ocular infection and immunity, little is known about the direct effects of IFN-γ on resident corneal cells or on the ocular surface. Here, we report that IFN-γ impacts corneal stromal fibroblasts and epithelial cells to promote inflammation, opacification, and barrier disruption on the ocular surface, leading to dry eye. Our results demonstrated that IFN-γ dose-dependently induced cytotoxicity, pro-inflammatory cytokine/chemokine production, and expression of major histocompatibility complex class II and CD40 in cultures of corneal stromal fibroblasts and epithelial cells while increasing myofibroblast differentiation of corneal stromal fibroblasts. In mice, subconjunctival IFN-γ administration caused corneal epithelial defects and stromal opacity in dose- and time-dependent manners while promoting neutrophil infiltration and inflammatory cytokine expression in the cornea. Moreover, IFN-γ reduced aqueous tear secretion and the number of conjunctival goblet cells responsible for mucinous tear production. Together, our findings suggest that IFN-γ induces the ocular surface changes characteristic of dry eye disease at least in part through its direct effects on resident corneal cells.

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Absence of Therapeutic Benefit of the Anti-Inflammatory Protein TSG-6 for Corneal Alkali Injury in a Rat Model

Cited by 6 publications

References 34 publications

TSG-6 in conditioned media from adipose mesenchymal stem cells protects against visual deficits in mild traumatic brain injury model through neurovascular modulation

TSG-6 in conditioned media from adipose mesenchymal stem cells protects against visual deficits in mild traumatic brain injury model through neurovascular modulation

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

Interferon-γ elicits the ocular surface pathology mimicking dry eye through direct modulation of resident corneal cells

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