Neurotrophins: Neuroimmune Interactions in Human Atopic Diseases

Weihrauch, Tobias; Limberg, Maren M.; Gray, Natalie; Schmelz, Martin; Raap, Ulrike

doi:10.3390/ijms24076105

Cited by 13 publications

(6 citation statements)

References 94 publications

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“…It also stimulates endothelial cells to enhance adhesion molecule expression and facilitate leukocyte infiltration ( 52 ). Additionally, β-NGF triggers mast cell degranulation and histamine release, while activating production of inflammatory mediators like substance P and calcitonin gene-related peptide (CGRP) ( 53 ). Overall, β-NGF plays a crucial role as a mediator of neuroinflammation and development of inflammatory hyperalgesia, exerting pro-inflammatory effects on both nerve and immune cells.…”

Section: Discussionmentioning

confidence: 99%

Causal association of circulating cytokines with sepsis: a Mendelian randomization study

Lin,

Mao,

2023

Front. Immunol.

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BackgroundObservational studies have reported an association between circulating cytokines and sepsis. However, the precise causal relationship between these factors remains unclear. The objective of this study was to explore the causal link between circulating cytokines and sepsis using genetic data within the framework of Mendelian Randomization (MR).MethodsWe performed a two-sample MR analysis to investigate this causality relationship in individuals of European ancestry. The publicly available genome-wide association studies (GWAS) statistics were used. We selected eligible instrumental single nucleotide polymorphisms (SNPs) that were significantly related to the circulating cytokines. Multiple MR analysis approaches were carried out, which included inverse variance weighted (IVW), Weighted Median, MR-Egger, Weighted Mode, Simple Mode, and MR pleiotropy residual sum and outlier (MR-PRESSO) methods.ResultsWe found evidence to support the causal role of genetically predicted circulating levels on decreased risk of sepsis, including RANTES (OR = 0.920, 95% CI: 0.849-0.997, P = 0.041) and basic fibroblast growth factor (basic-FGF) (OR = 0.869, 95% CI: 0.766-0.986, P = 0.029). Additionally, MR analysis positive causal association of between beta-nerve growth factor (β-NGF) and sepsis (OR = 1.120, 95% CI: 1.037-1.211, P = 0.004). The results of MR-Egger, Weighted Median, Weighted Mode, and Simple Mode methods were consistent with the IVW estimates. Sensitivity analysis showed no horizontal pleiotropy to bias the causal estimates.ConclusionThis MR study provides first novel evidence that genetically predicted causal association of circulating levels of RANTES, basic-FGF, and β-NGF with altered sepsis risk. The findings shed light on the potential involvement of these cytokines in sepsis pathogenesis. Although requiring additional confirmation, the results contribute new insights into cytokine mediators in sepsis and suggest promising future research directions.

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Section: Discussionmentioning

confidence: 99%

Causal association of circulating cytokines with sepsis: a Mendelian randomization study

Lin,

Mao,

2023

Front. Immunol.

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“…106 In addition, NGF can indirectly facilitate the sensation of itching by upregulating the expression of IL-4 from eosinophils and IL-13 from basophils. 107 Experiments conducted in NC/Nga mice have demonstrated the promising potential of targeting NGF and its receptors as a therapy for itch. 108,109 Similarly, CT327, a TrkA inhibitor, was shown to be effective in a phase 2b clinical trial for psoriasis.…”

Section: Axonal Guidance Moleculesmentioning

confidence: 99%

The involvement of keratinocytes in pruritus of chronic inflammatory dermatosis

Lin,

Liu,

Jiang

et al. 2024

Experimental Dermatology

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Frequent itching and incessant scratching are commonly observed in various chronic inflammatory skin conditions, including atopic dermatitis and psoriasis. The persistent and prolonged nature of pruritus can worsen one's quality of life. Keratinocytes (KCs), the predominant cells of the epidermis, have been confirmed to interact with sensory neurons and immune cells and be involved in chronic skin inflammatory diseases associated with pruritus. Initially, KCs and sensory neurons form a unique synapse‐like connection within the epidermis, serving as the structural foundation for their interaction. Additionally, several receptors, including toll‐like receptors and protease‐activated receptor 2, expressed on KCs, become activated in an inflammatory milieu. On the one hand, activated KCs are sources of pro‐inflammatory cytokines and neurotrophic factors, such as adenosine triphosphate, thymic stromal lymphopoietin, and nerve growth factor, which directly or indirectly participate in stimulating sensory neurons, thereby contributing to the itch sensations. On the other hand, KCs also function as primary transducers alongside intraepidermal nerve endings, directly initiating pruritic responses. This review summarizes the current literature and highlights the critical role of KCs in the development and persistence of chronic itch in inflammatory skin disorders.

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“…Notable effects of these neurotrophins are their role in increased responsiveness of peripheral neurons to normal or sub-threshold afferent stimulations ( Misery et al, 2023 ). BDNF is thought to be released by pruritogen-stimulated skin resident immune cells and binds to trkB which results in sprouting of peripheral nerves ( Weihrauch et al, 2023 ). Similarly, studies have also demonstrated a positive functional relationship between eosinophils expressing BDNF and nerve fiber outgrowth in itch sensitization ( Guseva et al, 2020 ).…”

Section: Peripheral Neural Sensitization In Chronic Itchmentioning

confidence: 99%

Itch: from the skin to the brain – peripheral and central neural sensitization in chronic itch

Mahmoud,

Oladipo,

Mahmoud

et al. 2023

Front. Mol. Neurosci.

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Similar to chronic pain, chronic itch is frequently linked to neural sensitization, a phenomenon wherein the nervous system becomes hypersensitive to stimuli. This process of neural sensitization of chronic itch is orchestrated by various signaling pathways and mediators in both the peripheral and central nervous systems. At the level of the peripheral nervous system, inflammation and neuroimmune interactions induce plastic changes to peripheral nerve fibers, thereby amplifying the transmission of itch signaling. Neural sensitization in the central nervous system occurs at both the spinal cord and brain levels. At the level of the spinal cord, it involves hyperactivity of itch-activating spinal pathways, dysfunction of spinal inhibitory circuits, and attenuation of descending supraspinal inhibitory pathways. In the brain, neural sensitization manifests as structural and functional changes to itch-associated brain areas and networks. Currently, we have a diverse array of neuroimmune-modulating therapies targeting itch neural sensitization mechanisms to help with providing relief to patients with chronic itch. Itch research is a dynamic and continually evolving field, and as we grow in our understanding of chronic itch mechanisms, so will our therapeutic toolbox. Further studies exploring the peripheral and central neural sensitization mechanisms in the context of chronic itch are needed.

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Neurotrophins: Neuroimmune Interactions in Human Atopic Diseases

Cited by 13 publications

References 94 publications

Causal association of circulating cytokines with sepsis: a Mendelian randomization study

Causal association of circulating cytokines with sepsis: a Mendelian randomization study

The involvement of keratinocytes in pruritus of chronic inflammatory dermatosis

Itch: from the skin to the brain – peripheral and central neural sensitization in chronic itch

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