Expression and Role of Nucleotide-Binding Oligomerization Domain 2 (NOD2) in the Ocular Surface of Murine Dry Eye

Li, Ying; Jin, Rujun; Li, Lan; Yoon, Hyeon Jeong; Choi, Joo-Hee; Park, Jong‐Hwan; Liu, Zuguo; Li, Wei; Li, Zhengri; Yoon, Kyung Chul

doi:10.1167/iovs.19-27144

Cited by 15 publications

(6 citation statements)

References 45 publications

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“…Recruitment of myeloid cells from the blood into the wounded intestinal mucosa and cornea of mice has been found to be CCR2 dependent (5)(6)(7). An increased percentage of CD11b + myeloid cells in the conjunctiva and cornea has been reported in the desiccating stress-induced murine dry eye model that develops SS like ocular surface disease, but it has not been established if these cells are recruited from the blood in a CCR2 dependent manner (8,9). An increase in antigen-presenting cells (APCs) and T cells in the conjunctiva of patients with SS KCS has been reported (10,11).…”

Section: Introductionmentioning

confidence: 99%

Desiccation Induced Conjunctival Monocyte Recruitment and Activation - Implications for Keratoconjunctivitis

2021

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BackgroundLacrimal gland secretory dysfunction in Sjögren syndrome (SS) causes ocular surface desiccation that is associated with increased cytokine expression and number of antigen-presenting cells (APCs) in the conjunctiva. This study evaluated the hypothesis that desiccating stress (DS) alters the percentage and gene expression of myeloid cell populations in the conjunctiva.MethodsDS was induced by pharmacologic suppression of tear secretion and exposure to drafty low humidity environment. Bone marrow chimeras and adoptive transfer of CD45.1+ bone marrow cells to CD45.2+ C-C chemokine receptor 2 knockout (CCR2-/-) mice were used to track DS-induced myeloid cell recruitment to the conjunctiva. Flow cytometry evaluated myeloid cell populations in conjunctivae obtained from non-stressed eyes and those exposed to DS for 5 days. CD11b+ myeloid lineage cells were gated on monocyte (Ly6C), macrophage (CD64, MHCII) and DC (CD11c, MHCII) lineage markers. NanoString immune arrays were performed on sorted MHCII+ and MHCII- monocyte/macrophage cell populations.ResultsDS significantly increased the recruitment of adoptively transferred MHCII positive and negative myeloid cells to the conjunctiva in a CCR2 dependent fashion. The percentage of resident conjunctival monocytes (Ly6C+CD64-) significantly decreased while CD64+MHCII+ macrophages increased over 5 days of DS (P<0.05 for both). Comparison of gene expression between the MHCII- monocyte and MHCII+ populations in non-stressed conjunctiva revealed a ≥ 2 log2 fold increase in 95 genes and decrease in 46 genes. Upregulated genes are associated with antigen presentation, cytokine/chemokine, M1 macrophage and NLRP3 inflammasome pathways. DS increased innate inflammatory genes in monocytes and MHCII+ cells and increased M1 macrophage (Trem1, Ido1, Il12b, Stat5b) and decreased homeostasis (Mertk) and M2 macrophage (Arg1) genes in MHCII+ cells.ConclusionsThere are myeloid cell populations in the conjunctiva with distinct phenotype and gene expression patterns. DS recruits myeloid cells from the blood and significantly changes their phenotype in the conjunctiva. DS also alters expression of an array of innate inflammatory genes. Immature monocytes in the unstressed conjunctiva appear to cascade to MHCII+ macrophages during DS, suggesting that DS promotes maturation of monocytes to antigen presenting cells with increased expression of inflammatory genes that may contribute to the pathogenesis of SS keratoconjunctivitis sicca.

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Section: Introductionmentioning

confidence: 99%

Desiccation Induced Conjunctival Monocyte Recruitment and Activation - Implications for Keratoconjunctivitis

2021

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“…Secondly, the increased expression of inflammatory cytokines may lead to goblet cell apoptosis and the occurrence of dry eye. Thirdly, related literature supports that IL-6 and TNF- α may activate downstream NF- κ B [ 8 ], p38MAPK [ 9 ], and JNK[ 10 ] pathways through TNF receptor 1 and activate downstream caspase-8[ 11 ] through TNF receptor 2 to induce apoptosis of functional cells ( Figure 3 ).…”

Section: Resultsmentioning

confidence: 94%

“…NF- κ B activation was an important regulator of TNF- α mediated apoptosis of corneal fibroblasts [ 19 ]. The activation of NF- κ B resulted in inflammation and apoptosis by on the ocular surface of dry eye, thereby reducing tear secretion [ 8 ]. TNF- α induces cell apoptosis by activating the p38 MAPK signaling pathway and acts as an effective TNF- α antagonist to prevent p38 MAPK-dependent apoptosis induced by TNF- α in cells [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

High Level of Inflammatory Cytokines in the Tears: A Bridge of Patients with Concomitant Exotropia and Dry Eye

Gao

Hong

Ding

et al. 2021

Oxidative Medicine and Cellular Longevity

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Concomitant exotropia have obvious symptoms of eye discomfort in adults, and the presence of ocular surface inflammation in patients may be important mediators between concomitant exotropia and dry eye. Oculus Keratograph eye comprehensive analyzer was performed to detect noninvasive tear break time, noninvasive tear height, and eye red index, while the ocular surface disease index and schirmer I testing were made. The levels of IL-6, IL-10, IL-17A, IL-12P70, INF-γ, and TNF-α were detected in tears in patients with concomitant exotropia and healthy controls matched by age and gender through the Simoa technology. IL-6 was significantly higher in patients with concomitant exotropia ( 4.683 ± 1.329 ) pg/mL than that in normal group ( 1.455 ± 0.391 ) pg/mL, p = 0.0304 . TNF-α was also significantly higher in patients ( 0.2095 ± 0.0703 ) pg/mL than normal group ( 0.0513 ± 0.0149 ) pg/mL, p = 0.0397 . The levels of inflammatory factors in strabismic patients vs. normal controls were as follows: IL-17A (0.1551 pg/mL︰0.0793 pg/mL), IL-10 (0.3358 pg/mL︰0.0513 pg/mL), IL-12p70 (0.0253 pg/mL︰0.0099 pg/mL), and INF-γ (0.0284 pg/mL︰0.009 pg/mL) were detected, and the median of them in concomitant strabismus was 1.96-6.55-fold as much as the control group. High levels of inflammatory cytokines in tears of patients with concomitant exotropia, which may be a potentially factor promoted the occurrence of dry eye in the patients with concomitant exotropia.

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“…no. 11836153001; Roche Diagnostics GmbH) on ice, and lysates were centrifuged at 25,200 x g for 10 min at 4˚C, as previously described (20). Proteins (20 µg) were separated by 12% SDS-PAGE and were transferred onto PVDF membranes.…”

Section: Methodsmentioning

confidence: 99%

Comparative analysis of 0.1% cyclosporin A cationic emulsion and 0.05% cyclosporin A emulsion in murine dry eye cases with different severities

Jin

et al. 2021

Exp Ther Med

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Dry eye (DE), especially severe DE (SDE), can cause ocular surface defects and reduce the patient's quality of life. Several clinical studies have shown that 0.1% cyclosporin A cationic emulsion (CsA CE) could decrease corneal damage. However, no experimental study has reported the effect of 0.1% CsA CE on SDE. The present study aimed to compare the efficacy of 0.1% CsA CE with that of 0.05% CsA emulsion for ocular surface damage and inflammation in the cases of murine DE with different severities. Following exposure to desiccating stress and subcutaneous injection of scopolamine for 5 days, C57BL/6 female mice were divided into SDE and non-SDE (NSDE) groups based on corneal fluorescein staining scores (CFSs). Mice from both groups were topically treated with 0.05% CsA emulsion or 0.1% CsA CE for 10 days. The results demonstrated that 0.1% CsA CE-treated mice in the SDE and NSDE groups exhibited significant improvements in all the clinical and experimental parameters. Furthermore, the CFS of 0.1% CsA CE-treated mice in the SDE group was lower compared with that of the 0.05% CsA-treated mice. In addition, in the SDE group, 0.1% CsA CE-treated mice had significantly lower levels of nuclear factor-κB activation, inflammatory infiltrations and apoptosis on the ocular surface, and they also exhibited higher conjunctival goblet cell density compared with the 0.05% CsA-treated mice. In summary, these findings indicated that 0.1% CsA CE was more effective than topical 0.05% CsA emulsion at improving corneal epithelial injury and decreasing the levels of inflammatory cytokines and T cells in mice with SDE.

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Expression and Role of Nucleotide-Binding Oligomerization Domain 2 (NOD2) in the Ocular Surface of Murine Dry Eye

Cited by 15 publications

References 45 publications

Desiccation Induced Conjunctival Monocyte Recruitment and Activation - Implications for Keratoconjunctivitis

Desiccation Induced Conjunctival Monocyte Recruitment and Activation - Implications for Keratoconjunctivitis

High Level of Inflammatory Cytokines in the Tears: A Bridge of Patients with Concomitant Exotropia and Dry Eye

Comparative analysis of 0.1% cyclosporin A cationic emulsion and 0.05% cyclosporin A emulsion in murine dry eye cases with different severities

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