Desiccation Induced Conjunctival Monocyte Recruitment and Activation - Implications for Keratoconjunctivitis

Alam, Jehan; Paiva, Cintia S. de; Pflugfelder, Stephen C.

doi:10.3389/fimmu.2021.701415

Cited by 16 publications

(17 citation statements)

References 30 publications

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“…SNPs in the MUC1 gene have been identified in SS and dry eye subjects (133)(134)(135). Interestingly, 5/50 upregulated genes in the conjunctiva of a mouse model of SS were also included in our upregulated DEGs [MX1, ICAM1, S100A9, IRF7, BATF, (136)].…”

Section: Genesmentioning

confidence: 99%

Differentially Expressed Gene Pathways in the Conjunctiva of Sjögren Syndrome Keratoconjunctivitis Sicca

et al. 2021

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Sjögren syndrome (SS) is an autoimmune condition that targets the salivary and lacrimal glands, with cardinal clinical signs of dry eye (keratoconjunctivitis sicca, KCS) and dry mouth. The conjunctiva of SS patients is often infiltrated by immune cells that participate in the induction and maintenance of local inflammation. The purpose of this study was to investigate immune-related molecular pathways activated in the conjunctiva of SS patients. Female SS patients (n=7) and controls (n=19) completed a series of oral, ocular surface exams. Symptom severity scores were evaluated using validated questionnaires (OSDI and SANDE). All patients fulfilled the ACR/EULAR criteria for SS and the criteria for KCS. Fluorescein and lissamine green dye staining evaluated tear-break-up time (TBUT), corneal and conjunctival disease, respectively. Impression cytology of the temporal bulbar conjunctiva was performed to collect cells lysed and subjected to gene expression analysis using the NanoString Immunology Panel. 53/594 differentially expressed genes (DEGs) were observed between SS and healthy controls; 49 DEGs were upregulated, and 4 were downregulated (TRAF5, TGFBI, KLRAP1, and CMKLRI). The top 10 DEGs in descending order were BST2, IFITM1, LAMP3, CXCL1, IL19, CFB, LY96, MX1, IL4R, CDKN1A. Twenty pathways had a global significance score greater or equal to 2. Spearman correlations showed that 29/49 upregulated DEGs correlated with either TBUT (inverse) or OSDI or conjunctival staining score (positive correlations). Venn diagrams identified that 26/29 DEGs correlated with TBUT, 5/26 DEGs correlated with OSDI, and 16/26 correlated with conjunctival staining scores. Five upregulated DEGs (CFB, CFI, IL1R1, IL2RG, IL4R) were uniquely negatively correlated with TBUT. These data indicate that the conjunctiva of SS patients exhibits a phenotype of immune activation, although some genes could be inhibitory. Some of the DEGs and pathways overlap with previous DEGs in salivary gland biopsies, but new DEGs were identified, and some of these correlated with symptoms and signs of dry eye. Our results indicate that gene analysis of conjunctiva imprints is a powerful tool to understand the pathogenesis of SS and develop new therapeutic targets.

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Section: Genesmentioning

confidence: 99%

Differentially Expressed Gene Pathways in the Conjunctiva of Sjögren Syndrome Keratoconjunctivitis Sicca

et al. 2021

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“…The recruitment or activation of NK cells at the ocular surface enhances the production of inflammatory cytokines such as interferon-γ (IFN-γ), IL-6 and Th17-related IL-17, which stimulate macrophages, antigen presenting cells (APC) and autoreactive T lymphocytes. IFN-γ is responsible for T helper 1 (Th1) cell activation and differentiation, and can cause cell-mediated conjunctival epithelial damage and goblet cell loss ( 26 ). Monocytes infiltrated to the conjunctiva can be differentiated into two subtypes of macrophages: M1 cells associated with pro-inflammatory responses and M2 cells responsible for immunoregulation.…”

Section: Immunomodulation Of Dry Eye Diseasementioning

confidence: 99%

Current Advances in Mechanisms and Treatment of Dry Eye Disease: Toward Anti-inflammatory and Immunomodulatory Therapy and Traditional Chinese Medicine

et al. 2022

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Dry eye is currently one of the most common ocular surface disease. It can lead to ocular discomfort and even cause visual impairment, which greatly affects the work and quality of life of patients. With the increasing incidence of dry eye disease (DED) in recent years, the disease is receiving more and more attention, and has become one of the hot research fields in ophthalmology research. Recently, with the in-depth research on the etiology, pathogenesis and treatment of DED, it has been shown that defects in immune regulation is one of the main pathological mechanisms of DED. Since the non-specific and specific immune response of the ocular surface are jointly regulated, a variety of immune cells and inflammatory factors are involved in the development of DED. The conventional treatment of DED is the application of artificial tears for lubricating the ocular surface. However, for moderate-to-severe DED, treatment with anti-inflammatory drugs is necessary. In this review, the immunomodulatory mechanisms of DED and the latest research progress of its related treatments including Chinese medicine will be discussed.

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“…Using a murine model with DED induced by a desiccating environment and scopolamine to maximally reduce tear production, the distribution of pro-inflammatory M1 macrophages on the ocular surface has been investigated, and M1 macrophages were found to predominantly reside in the conjunctiva [6]. Notably, the subconjunctival injection of clodronate to locally deplete the resident conjunctival macrophages significantly reduces ocular surface damage and proinflammatory cytokine expression in dry eyes [7,8]. A mouse model of desiccating stressinduced dry eyes is shown to recruit monocytes into the conjunctiva and to induce them into activated macrophages [7,8].…”

Section: Introductionmentioning

confidence: 99%

“…Notably, the subconjunctival injection of clodronate to locally deplete the resident conjunctival macrophages significantly reduces ocular surface damage and proinflammatory cytokine expression in dry eyes [7,8]. A mouse model of desiccating stressinduced dry eyes is shown to recruit monocytes into the conjunctiva and to induce them into activated macrophages [7,8]. The activated macrophages have upregulated expression of the genes that are associated with antigen presentation, cytokines/chemokines, M1 macrophages, and the NLRP3 inflammasome pathway [8].…”

Section: Introductionmentioning

confidence: 99%

“…A mouse model of desiccating stressinduced dry eyes is shown to recruit monocytes into the conjunctiva and to induce them into activated macrophages [7,8]. The activated macrophages have upregulated expression of the genes that are associated with antigen presentation, cytokines/chemokines, M1 macrophages, and the NLRP3 inflammasome pathway [8]. These activities further enhance the inflammatory status of the ocular surface.…”

Section: Introductionmentioning

confidence: 99%

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

Yeh

Chen

et al. 2021

IJMS

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Cell signaling mediated by the αv integrin plays a pivotal role in macrophage activation in various inflammatory processes, but its involvement in the pathogenesis of dry eye disease (DED) remains unclear. In a murine model of DED, we found increased αv integrin expression in ocular surface macrophages. The αv integrins inhibitor c(RGDfK) ameliorated the corneal damage caused by DED, suggesting a pathogenic role for αv integrin. Because tear hyperosmolarity induces ocular inflammation in DED, a hyperosmolar culture of murine bone marrow-derived macrophages (BMDMs) is used to reproduce inflammation in vitro. However, the expression of proinflammatory cytokine mRNA was minimal, even though αv integrin was induced. In searching for components that are involved in αv integrin-mediated inflammation but that are missing from the culture model, we showed that the levels of vitronectin (VTN), a binding ligand of αv integrins, were increased in the tear fluid and conjunctival stroma of DED animals. The addition of VTN prominently enhanced hyperosmolarity-induced inflammation in BMDMs. Mechanistically, we showed that VTN/αv integrins mediated NF-κB activation to induce inflammatory gene expression in the BMDMs. Our findings indicate that interaction the of VTN with αv integrins is a crucial step in the inflammatory process in DED and suggests a novel therapeutic target.

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Desiccation Induced Conjunctival Monocyte Recruitment and Activation - Implications for Keratoconjunctivitis

Cited by 16 publications

References 30 publications

Differentially Expressed Gene Pathways in the Conjunctiva of Sjögren Syndrome Keratoconjunctivitis Sicca

Differentially Expressed Gene Pathways in the Conjunctiva of Sjögren Syndrome Keratoconjunctivitis Sicca

Current Advances in Mechanisms and Treatment of Dry Eye Disease: Toward Anti-inflammatory and Immunomodulatory Therapy and Traditional Chinese Medicine

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

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