Integrin αv and Vitronectin Prime Macrophage-Related Inflammation and Contribute the Development of Dry Eye Disease

Ho, Tzyy‐Chang; Yeh, Shu‐I; Chen, Show‐Li; Tsao, Yeou‐Ping

doi:10.3390/ijms22168410

Cited by 18 publications

(21 citation statements)

References 38 publications

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“…This will be an important step in the inflammatory process of dry eye disease (DED). 551 In addition, drug discovery focused on integrin αlβ2, providing a marketed small molecule, LifiteGrast, for the topical treatment of DED. 552 For ophthalmic diseases, integrin inhibitors were proven to be effective in several preclinical models and have reported promising results in clinical trials.…”

Section: Integrin Roles In Physiology and Pathologymentioning

confidence: 99%

Targeting integrin pathways: mechanisms and advances in therapy

Pang

Qiu

et al. 2023

Sig Transduct Target Ther

334

111

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Integrins are considered the main cell-adhesion transmembrane receptors that play multifaceted roles as extracellular matrix (ECM)-cytoskeletal linkers and transducers in biochemical and mechanical signals between cells and their environment in a wide range of states in health and diseases. Integrin functions are dependable on a delicate balance between active and inactive status via multiple mechanisms, including protein-protein interactions, conformational changes, and trafficking. Due to their exposure on the cell surface and sensitivity to the molecular blockade, integrins have been investigated as pharmacological targets for nearly 40 years, but given the complexity of integrins and sometimes opposite characteristics, targeting integrin therapeutics has been a challenge. To date, only seven drugs targeting integrins have been successfully marketed, including abciximab, eptifibatide, tirofiban, natalizumab, vedolizumab, lifitegrast, and carotegrast. Currently, there are approximately 90 kinds of integrin-based therapeutic drugs or imaging agents in clinical studies, including small molecules, antibodies, synthetic mimic peptides, antibody–drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, imaging agents, etc. A serious lesson from past integrin drug discovery and research efforts is that successes rely on both a deep understanding of integrin-regulatory mechanisms and unmet clinical needs. Herein, we provide a systematic and complete review of all integrin family members and integrin-mediated downstream signal transduction to highlight ongoing efforts to develop new therapies/diagnoses from bench to clinic. In addition, we further discuss the trend of drug development, how to improve the success rate of clinical trials targeting integrin therapies, and the key points for clinical research, basic research, and translational research.

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Section: Integrin Roles In Physiology and Pathologymentioning

confidence: 99%

Targeting integrin pathways: mechanisms and advances in therapy

Pang

Qiu

et al. 2023

Sig Transduct Target Ther

334

111

View full text Add to dashboard Cite

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“…Macrophages are key immune cells recruited to the cornea during ocular surface disease. Under pathological conditions, macrophages are stimulated by hyperosmotic stress, initiate inflammatory responses [ 45 ], and are polarized toward the M1 phenotype [ 35 , 46 ]. To test whether IL-20 alters macrophage activation, we incubated murine BMDMs with hyperosmotic stress and analyzed the effects of 7E.…”

Section: Resultsmentioning

confidence: 99%

“…Fifty-six female C57BL/6 mice (22–25 g; 8 weeks old) were placed in a controlled environment chamber (CEC) (relative humidity < 25%, 24–25 °C temperature, 24 h per day) to induce desiccating stress so that the mice’s tears were excessively evaporated as previously reported [ 35 ]. The experimental procedures were according to the guidelines set forth by the Council for International Organization of Medical Sciences on Animal Experimentation and the guidelines set forth by National Cheng Kung University (IACUC Approval No: 110345).…”

Section: Methodsmentioning

confidence: 99%

Interleukin-20 is involved in dry eye disease and is a potential therapeutic target

et al. 2022

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Background Dry eye disease (DED) is a common disease in ophthalmology, affecting millions of people worldwide. Recent studies have shown that inflammation is the core mechanism of DED. IL-20 is a proinflammatory cytokine involved in various inflammatory diseases. Therefore, we aimed to explore the role of this cytokine in the pathogenesis of DED and evaluate the therapeutic potential of the anti-IL-20 monoclonal antibody (mAb) 7E for DED treatment. Methods Clinical tear samples from patients with DED and non-DED controls were collected and their IL-20 protein levels were determined. We established three DED animal models to explore the role of IL-20 and the efficacy of IL-20 antibody in DED. Benzalkonium chloride (BAC)-induced over-evaporative DED, extra-orbital lacrimal gland excision (LGE)-induced aqueous tear-deficient DED, and desiccating stress (DS)-induced combined over-evaporative and aqueous tear-deficient DED animal models were established to investigate the role of IL-20. The anti-IL-20 antibody 7E was established to neutralize IL-20 activity. The effects of IL-20 or 7E on human corneal epithelial cells and macrophages under hyperosmotic stress were analyzed. 7E was topically applied to eyes to evaluate the therapeutic effects in the DED animal models. Results IL-20 was significantly upregulated in the tears of patients with DED and in the tears and corneas of DED animal models. Under hyperosmotic stress, IL-20 expression was induced via NFAT5 activation in corneal epithelial cells. 7E suppressed hyperosmotic stress-induced activation of macrophages. IL-20 induced cell death in corneal epithelial cells and 7E protected cells from hyperosmotic stress-induced cell death. Blocking IL-20 signaling with 7E protected mice from BAC-induced, LGE-induced, and DS-induced DED by reducing DED symptoms and inhibiting inflammatory responses, macrophage infiltration, apoptosis, and Th17 populations in the conjunctiva and draining lymph nodes. Conclusions Our results demonstrated the functions of IL-20 in DED and presented a potential therapeutic option for this condition. Graphical Abstract

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“…Notably, the binding of vitronectin to av integrins on macrophages also induces nuclear transcription factor kappa B (NF-kB)-mediated expression of the inflammatory cytokines TNF-a, IL1b and IL6 (Figure 1), as demonstrated by experiments with bone marrow-derived murine macrophages (109). Vitronectin-dependent expression of IL6 and leukemia inhibitory factor (LIF) was also observed in cultured endothelial and glial cells as well as in mouse brains after treatment with recombinant vitronectin (115).…”

Section: Vitronectinmentioning

confidence: 98%

The extracellular microenvironment in immune dysregulation and inflammation in retinal disorders

et al. 2023

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Inherited retinal dystrophies (IRDs) as well as genetically complex retinal phenotypes represent a heterogenous group of ocular diseases, both on account of their phenotypic and genotypic characteristics. Therefore, overlaps in clinical features often complicate or even impede their correct clinical diagnosis. Deciphering the molecular basis of retinal diseases has not only aided in their disease classification but also helped in our understanding of how different molecular pathologies may share common pathomechanisms. In particular, these relate to dysregulation of two key processes that contribute to cellular integrity, namely extracellular matrix (ECM) homeostasis and inflammation. Pathological changes in the ECM of Bruch’s membrane have been described in both monogenic IRDs, such as Sorsby fundus dystrophy (SFD) and Doyne honeycomb retinal dystrophy (DHRD), as well as in the genetically complex age-related macular degeneration (AMD) or diabetic retinopathy (DR). Additionally, complement system dysfunction and distorted immune regulation may also represent a common connection between some IRDs and complex retinal degenerations. Through highlighting such overlaps in molecular pathology, this review aims to illuminate how inflammatory processes and ECM homeostasis are linked in the healthy retina and how their interplay may be disturbed in aging as well as in disease.

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Integrin αv and Vitronectin Prime Macrophage-Related Inflammation and Contribute the Development of Dry Eye Disease

Cited by 18 publications

References 38 publications

Targeting integrin pathways: mechanisms and advances in therapy

Targeting integrin pathways: mechanisms and advances in therapy

Interleukin-20 is involved in dry eye disease and is a potential therapeutic target

The extracellular microenvironment in immune dysregulation and inflammation in retinal disorders

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