Corneal Denervation Causes Epithelial Apoptosis Through Inhibiting NAD<sup>+</sup> Biosynthesis

Li, Ya; Ma, Xiubin; Li, Jing; Yang, Lingling; Zhao, Xiaowen; Qi, Xia; Zhang, Xiaoping; Zhou, Qingjun; Shi, Weiyun

doi:10.1167/iovs.19-26909

Cited by 17 publications

(9 citation statements)

References 45 publications

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“…In two most recent experiments, it was found that NMN application could promote epithelial homeostasis by regulating the biosynthesis of NAD+. 15 Besides, local supplementation of NMN can effectively prevent corneal endothelial cell apoptosis from UVB exposure by reactivating AKT signaling. 16 To detect the effects of NMN on the CECmacrophage interaction in the development of DED, we conduct an in-vitro study and the aims of this study included (1) detection of the protective effects of NMN on HS-induced CEC and (2) clarification of the effects of IL-17a on biological functions of macrophage.…”

Section: Introductionmentioning

confidence: 99%

Nicotinamide Mononucleotide Alleviates Hyperosmolarity-Induced IL-17a Secretion and Macrophage Activation in Corneal Epithelial Cells/Macrophage Co-Culture System

Yu¹,

Pu²,

Dai³

et al. 2021

JIR

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Background Hyperosmosis stress (HS) was a key pathological factor in the development of dry eye disease (DED). Nicotinamide mononucleotide (NMN) demonstrated protective effects in the corneal damage, however, its role in the HS-induced DED remained unclear. Methods A NaCl based HS in-vitro model (500 mOsm) was generated and used in a co-culture system including corneal epithelial cells (CEC) and macrophage cell line RAW264.7. The effect of NMN on NAD+ metabolism and the expression of HS biomarker, tonicity-responsive element binding protein (TonEBP), was studied in the CEC. The cellular activity, including cell viability, apoptosis status and lactate dehydrogenase (LDH) release through trypan blue staining, flow cytometry and LDH assay, respectively. The mitochondrial membrane potential (MMP) assay would be conducted using the JC1 kit. The expression of IL-17a were detected using RT-PCR, ELISA and Western blot. After co-culture with the CEC in different group for 24 h, the phagocytosis ability and macrophage polarization were assessed in RAW264.7 cells co-cultured with CEC with or without HS or NMN treatment. Besides, the involvement of Notch pathway in the RAW264.7 would be analyzed. The potential involvement of Sirtuin 1 (SIRT1) and IL-17a in the crosstalk between CEC and macrophage was studied with SIRT1 inhibitor EX 527 and anti-IL-17a monoclonal antibody, respectively. Results NMN treatment increased NAD+ concentration and thus improved cell viability, reduced apoptotic rate and decreased the LDH release in HS-treated CEC. Besides, NMN alleviated HS-induced MMP, intracellular ROS and LDH release. Besides, it was confirmed NMN improve SIRT1 function and decreased the HS related IL-17a expression in CEC and then alleviated macrophage phagocytosis ability and M1 polarization based on a CEC-macrophage co-culture system. Moreover, NMN treatment of CEC in the CEC could moderate the subsequent macrophage activation through Notch pathway. SIRT1 activation and IL-17a inhibition was regarded as key progress in the function of NMN based on the application of EX 527 and anti-IL-17a antibody in the CEC-macrophage co-culture system. Conclusion The findings demonstrated that NMN could alleviated HS-induced DED status through regulating the CEC/macrophage interaction. Our data pointed to the role of SIRT1, IL-17a and Notch pathway in the function of NMN and then provided updated knowledge of potential NMN application in the management of DED.

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Section: Introductionmentioning

confidence: 99%

Nicotinamide Mononucleotide Alleviates Hyperosmolarity-Induced IL-17a Secretion and Macrophage Activation in Corneal Epithelial Cells/Macrophage Co-Culture System

Yu¹,

Pu²,

Dai³

et al. 2021

JIR

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“…19 In corneal epithelial cells, denervation causes epithelial apoptosis. 24 This is also evident in dermal models where keratinocyte proliferation was induced by coculturing keratinocytes with neurons, but was reversed by inhibition of CGRP, but not substance P. 25 Similar to murine nasal epithelium, 8 we found that SCCs in human inferior turbinate epithelium are intimately associated with CGRP-reactive nerve endings, which was not evident in human nasal polyps. Recent proteomic analysis of eosinophilic polyps demonstrated downregulation of proteins associated with the axonal guidance signaling pathway and upregulation of proteins associated with axonal growth inhibition.…”

Section: Discussionmentioning

confidence: 55%

“…The intimate relationship of nerve fibers in the epithelium is suggested to be essential for epithelial homeostatic maintenance. 19 In corneal epithelial cells, denervation causes epithelial apoptosis. 24 This is also evident in dermal models where keratinocyte proliferation was induced by coculturing keratinocytes with neurons, but was reversed by inhibition of CGRP, but not substance P.…”

Section: Discussionmentioning

confidence: 99%

Solitary chemosensory cells are innervated by trigeminal nerve endings and autoregulated by cholinergic receptors

Tan

Kohanski

Kennedy

et al. 2020

Int Forum Allergy Rhinol

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Background Solitary chemosensory cells SCCs in the murine nasal epithelium are discrete specialized cells that respond to irritants and activate trigeminal nerve fibers through the release of acetylcholine ACh resulting in local neurogenic inflammation In addition to releasing ACh SCCs are the exclusive epithelial source of interleukin IL -In humans SCCs are significantly expanded in sinonasal polyps NPs However the SCC-trigeminal synapse has yet to be demonstrated in human sinonasal epithelium Methods Immunofluorescence for trigeminal nerve fiber markers nicotinic ACh receptors nChR and SCC markers was performed in vibratome sections from polyp and healthy turbinate tissue Quantitative polymerase chain reaction and immunofluorescence of cultured epithelial cells were used to evaluate the expansion of SCCs Last intracellular calcium imaging was used to demonstrate cholinergic signaling in sinonasal epithelial cells Results Calcitonin gene-related peptide CGRP immunostaining was used to identify cholinergic nerve endings which were only evident in sections from the inferior turbinate and intertwined with SCCs α-gustducin-positive cells CGRP-positive nerve endings were not identified in sections from NPs Human SCCs expressed nChR as well as the ACh synthetic enzyme choline acetyltransferase Live cell calcium imaging demonstrated functionally active cholinergic signaling in discrete sinonasal epithelial cells consistent with SCCs Finally SCC-specific genes were dramatically upregulated with pretreatment with IL-and nicotinic agonists Conclusion SCCs are innervated by trigeminal nerve endings in healthy turbinate tissue but not in NPs SCCs express ACh receptors as well as choline acetyltransferase and in the setting of a type inflammatory environment denervated SCCs dramatically expand with nicotinic stimulation © 2020 ARS-AAOA, LLC.

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“…Diseases. In addition, to the major sight-threatening retinal diseases mentioned previously, alterations in NAD + metabolism have been reported to occur also in association with other retinal and nonretinal ocular diseases including diabetic retinopathy [101], retinal vein occlusion [23], neurotrophic keratopathy [102], and traumatic optic neuropathy [103]. A brief mention of current information available relevant to these ocular disorders is provided below.…”

Section: The Relevance Of Nad + Metabolism In Other Eyementioning

confidence: 98%

“…The incidence of neurotrophic keratitis increases with age. To determine how corneal epithelial denervation induces apoptosis, Li et al [102] studied the significance of NAD + levels and NAMPT expression in a mouse model of corneal denervation. The results showed that the denervation decreased epithelial NAD + content by reducing NAMPT expression resulting in corneal epithelial apoptosis.…”

Section: The Relevance Of Nad + Metabolism In Other Eyementioning

confidence: 99%

Implications of NAD⁺ Metabolism in the Aging Retina and Retinal Degeneration

Jadeja

Thounaojam

Bartoli

et al. 2020

Oxidative Medicine and Cellular Longevity

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Nicotinamide adenine dinucleotide (NAD+) plays an important role in various key biological processes including energy metabolism, DNA repair, and gene expression. Accumulating clinical and experimental evidence highlights an age-dependent decline in NAD+ levels and its association with the development and progression of several age-related diseases. This supports the establishment of NAD+ as a critical regulator of aging and longevity and, relatedly, a promising therapeutic target to counter adverse events associated with the normal process of aging and/or the development and progression of age-related disease. Relative to the above, the metabolism of NAD+ has been the subject of numerous investigations in various cells, tissues, and organ systems; however, interestingly, studies of NAD+ metabolism in the retina and its relevance to the regulation of visual health and function are comparatively few. This is surprising given the critical causative impact of mitochondrial oxidative damage and bioenergetic crises on the development and progression of degenerative disease of the retina. Hence, the role of NAD+ in this tissue, normally and aging and/or disease, should not be ignored. Herein, we discuss important findings in the field of NAD+ metabolism, with particular emphasis on the importance of the NAD+ biosynthesizing enzyme NAMPT, the related metabolism of NAD+ in the retina, and the consequences of NAMPT and NAD+ deficiency or depletion in this tissue in aging and disease. We discuss also the implications of potential therapeutic strategies that augment NAD+ levels on the preservation of retinal health and function in the above conditions. The overarching goal of this review is to emphasize the importance of NAD+ metabolism in normal, aging, and/or diseased retina and, by so doing, highlight the necessity of additional clinical studies dedicated to evaluating the therapeutic utility of strategies that enhance NAD+ levels in improving vision.

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Corneal Denervation Causes Epithelial Apoptosis Through Inhibiting NAD⁺ Biosynthesis

Cited by 17 publications

References 45 publications

Nicotinamide Mononucleotide Alleviates Hyperosmolarity-Induced IL-17a Secretion and Macrophage Activation in Corneal Epithelial Cells/Macrophage Co-Culture System

Nicotinamide Mononucleotide Alleviates Hyperosmolarity-Induced IL-17a Secretion and Macrophage Activation in Corneal Epithelial Cells/Macrophage Co-Culture System

Solitary chemosensory cells are innervated by trigeminal nerve endings and autoregulated by cholinergic receptors

Implications of NAD⁺ Metabolism in the Aging Retina and Retinal Degeneration

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Corneal Denervation Causes Epithelial Apoptosis Through Inhibiting NAD+ Biosynthesis

Cited by 17 publications

References 45 publications

Nicotinamide Mononucleotide Alleviates Hyperosmolarity-Induced IL-17a Secretion and Macrophage Activation in Corneal Epithelial Cells/Macrophage Co-Culture System

Nicotinamide Mononucleotide Alleviates Hyperosmolarity-Induced IL-17a Secretion and Macrophage Activation in Corneal Epithelial Cells/Macrophage Co-Culture System

Solitary chemosensory cells are innervated by trigeminal nerve endings and autoregulated by cholinergic receptors

Implications of NAD+ Metabolism in the Aging Retina and Retinal Degeneration

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Corneal Denervation Causes Epithelial Apoptosis Through Inhibiting NAD⁺ Biosynthesis

Implications of NAD⁺ Metabolism in the Aging Retina and Retinal Degeneration