The impact of sensory neuropathy and inflammation on epithelial wound healing in diabetic corneas

Yu, Fu–Shin X.; Lee, Patrick S Y; Yang, Lingling; Gao, Nan; Zhang, Yangyang; Ljubimov, Alexander V.; Yang, Ellen; Zhou, Qingjun; Xie, Lixin

doi:10.1016/j.preteyeres.2021.101039

Cited by 72 publications

(58 citation statements)

References 362 publications

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“…On the contrary, some literature showed the opposite findings in which decreased corneal DCs were observed in both animal models and patients with T1D/T2D (59,78,79). One proposed explanation is that prolonged exposure to hyperglycaemia may cause DC apoptosis, reducing the DCs density (80). Similar observations in other immune cells, such as increased apoptosis in neutrophils as well as impaired antigen presentation by monocytes, have also been reported under chronic hyperglycaemic conditions (81).…”

Section: Stz-induced T1d Mice Whole-mount Confocal Microscopy (Wmcm)supporting

confidence: 56%

“…Diabetes may perturb the interaction between DCs and other structures, especially corneal nerves (80). In the confocal images of mouse corneas stained with CD11c (inflammatory marker) and btubulin 3 (neuronal marker), intimate contacts between the DC body and its processes with sensory nerve endings were observed (59).…”

Section: Associations Between Corneal Dcs and Corneal Nervesmentioning

confidence: 99%

“…Reciprocally, the immune cells recognise the neurotransmitters and neuropeptides produced by the corneal nerves (95). It is speculated that the DC-nerve interaction in the cornea may be analogous to the neuro-immune axis in the skin and the gut (49,80). For example, it was demonstrated that calcitonin gene-related peptide (CGRP)-containing nerve fibres were intimately associated with DCs and that CGRP could inhibit antigen presentation by epidermal DCs (96).…”

Section: Associations Between Corneal Dcs and Corneal Nervesmentioning

confidence: 99%

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Corneal dendritic cells in diabetes mellitus: A narrative review

Liu

Lee

et al. 2023

Front. Endocrinol.

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Diabetes mellitus is a global public health problem with both macrovascular and microvascular complications, such as diabetic corneal neuropathy (DCN). Using in-vivo confocal microscopy, corneal nerve changes in DCN patients can be examined. Additionally, changes in the morphology and quantity of corneal dendritic cells (DCs) in diabetic corneas have also been observed. DCs are bone marrow-derived antigen-presenting cells that serve both immunological and non-immunological roles in human corneas. However, the role and pathogenesis of corneal DC in diabetic corneas have not been well understood. In this article, we provide a comprehensive review of both animal and clinical studies that report changes in DCs, including the DC density, maturation stages, as well as relationships between the corneal DCs, corneal nerves, and corneal epithelium, in diabetic corneas. We have also discussed the associations between the changes in corneal DCs and various clinical or imaging parameters, including age, corneal nerve status, and blood metabolic parameters. Such information would provide valuable insight into the development of diagnostic, preventive, and therapeutic strategies for DM-associated ocular surface complications.

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Section: Stz-induced T1d Mice Whole-mount Confocal Microscopy (Wmcm)supporting

confidence: 56%

Section: Associations Between Corneal Dcs and Corneal Nervesmentioning

confidence: 99%

Section: Associations Between Corneal Dcs and Corneal Nervesmentioning

confidence: 99%

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Corneal dendritic cells in diabetes mellitus: A narrative review

Liu

Lee

et al. 2023

Front. Endocrinol.

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“…However, hyperglycemia essentially disrupts these interdependencies, leading to inhibited epithelial proliferation, sensory neuropathy, and decreased dendritic cell density, which causes significant delays in wound healing and sensory nerve repair (8). Although the pathogenesis of T1DM is different from that of T2DM, hyperglycemia is a common feature of diabetes, and low-grade inflammation is a potential mechanism for diabetic complications (9). In the inflammatory process, the imbalance between inflammatory factors and growth factors in diabetic patients is the cause of the chronic inflammatory reaction of the wound (10).…”

Section: Introductionmentioning

confidence: 99%

Fibroblasts: Immunomodulatory factors in refractory diabetic wound healing

Liu

et al. 2022

Front. Immunol.

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Diabetes is a systemic disease in which patients with diabetes may develop peripheral neuropathy of the lower extremities and peripheral vascular disease due to long-term continuous exposure to high glucose. Delayed wound healing in diabetes is one of the major complications of diabetes. Slow wound healing in diabetic patients is associated with high glucose toxicity. When the condition deteriorates, the patient needs to be amputated, which seriously affects the quality of life and even endangers the life of the patient. In general, the delayed healing of diabetes wound is due to the lack of chemokines, abnormal inflammatory response, lack of angiogenesis and epithelial formation, and fibroblast dysfunction. The incidence of several chronic debilitating conditions is increasing in patients with diabetes, such as chronic renal insufficiency, heart failure, and hepatic insufficiency. Fibrosis is an inappropriate deposition of extracellular matrix (ECM) proteins. It is common in diabetic patients causing organ dysfunction. The fibrotic mechanism of diabetic fibroblasts may involve direct activation of permanent fibroblasts. It may also involve the degeneration of fibers after hyperglycemia stimulates immune cells, vascular cells, or organ-specific parenchymal cells. Numerous studies confirm that fibroblasts play an essential role in treating diabetes and its complications. The primary function of fibroblasts in wound healing is to construct and reshape the ECM. Nowadays, with the widespread use of single-cell RNA sequencing (scRNA-seq), an increasing number of studies have found that fibroblasts have become the critical immune sentinel cells, which can detect not only the activation and regulation of immune response but also the molecular pattern related to the injury. By exploring the heterogeneity and functional changes of fibroblasts in diabetes, the manuscript discusses that fibroblasts may be used as immunomodulatory factors in refractory diabetic wound healing, providing new ideas for the treatment of refractory diabetic wound healing.

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“…Recent studies uncovered that sensory neuropeptide could participate in multiple organ physiology and pathophysiology processes such as wound healing, inflammatory responses, and energy metabolism. [ 15 , 16 , 17 ] By mass spectrum analysis, we detected high level of sensory neuropeptide calcitonin gene‐related peptide (CGRP) secretion in mice lumbar dorsal root ganglia (DRG). CGRP was reported to be able to promote osteoblastic bone matrix deposition, [ 18 ] suggesting its potential pro‐anabolic role.…”

Section: Introductionmentioning

confidence: 99%

Sensory Nerve Maintains Intervertebral Disc Extracellular Matrix Homeostasis Via CGRP/CHSY1 Axis

Wei

et al. 2022

Advanced Science

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Sensory nerves are long being recognized as collecting units of various outer stimuli; recent advances indicate that the sensory nerve also plays pivotal roles in maintaining organ homeostasis. Here, this study shows that sensory nerve orchestrates intervertebral disc (IVD) homeostasis by regulating its extracellular matrix (ECM) metabolism. Specifically, genetical sensory denervation of IVD results in loss of IVD water preserve molecule chondroitin sulfate (CS), the reduction of CS bio‐synthesis gene chondroitin sulfate synthase 1 (CHSY1) expression, and dysregulated ECM homeostasis of IVD. Particularly, knockdown of sensory neuros calcitonin gene‐related peptide (CGRP) expression induces similar ECM metabolic disorder compared to sensory nerve denervation model, and this effect is abolished in CHSY1 knockout mice. Furthermore, in vitro evidence shows that CGRP regulates nucleus pulposus cell CHSY1 expression and CS synthesis via CGRP receptor component receptor activity‐modifying protein 1 (RAMP1) and cyclic AMP response element‐binding protein (CREB) signaling. Therapeutically, local injection of forskolin significantly attenuates IVD degeneration progression in mouse annulus fibrosus puncture model. Overall, these results indicate that sensory nerve maintains IVD ECM homeostasis via CGRP/CHSY1 axis and promotes IVD repair, and this expands the understanding concerning how IVD links to sensory nerve system, thus shedding light on future development of novel therapeutical strategy to IVD degeneration.

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The impact of sensory neuropathy and inflammation on epithelial wound healing in diabetic corneas

Cited by 72 publications

References 362 publications

Corneal dendritic cells in diabetes mellitus: A narrative review

Corneal dendritic cells in diabetes mellitus: A narrative review

Fibroblasts: Immunomodulatory factors in refractory diabetic wound healing

Sensory Nerve Maintains Intervertebral Disc Extracellular Matrix Homeostasis Via CGRP/CHSY1 Axis

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