Neurogenic inflammation and urticaria: Unraveling the mind–skin connection: A comprehensive review

Inclusion criteria

The selection criteria included original studies, clinical trials, reviews, and case series published in English. These studies involved human subjects or relevant in vivo or in vitro models. In addition, the articles focused on neuropeptides, nervous system involvement, or psychoneuroimmunology in urticaria.

Exclusion criteria

Articles that are not related to urticaria or do not discuss neurogenic or psychoneuroimmune mechanisms, as well as letters to the editor or opinion pieces without data, were excluded. A total of 142 articles were screened, and 78 were included in this review based on relevance and quality. Reference lists of included studies were also manually screened to identify additional sources.

SP

SP is a member of the tachykinin family and a key mediator of neurogenic inflammation. It is synthesized in dorsal root ganglia and released from C-fiber nerve endings.

CGRP

CGRP is a 37 aminoacid neuropeptide released from both sensory and sympathetic nerves. Although its role in CSU is less well defined than SP, CGRP induces vasodilatation and synergizes with SP to potentiate plasma extravasation. It also promotes nitricoxide production and modulates Tcell and dendriticcell function. Elevated CGRP levels have been reported in patients with chronic itch, but further studies are needed to clarify its contribution to urticaria.^[12]

VIP

VIP is a neuropeptide with potent immunomodulatory effects. It stimulates cyclic AMP production in mast cells, enhancing histamine release in some settings. VIP also increases interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) production, and modulates T-cell polarization toward a Th2 phenotype.^[13]

Key cytokines and mediators

In addition to neuropeptides, several cytokines and mediators are critical in CSU pathophysiology. IL6 and TNFα drive inflammatory cell recruitment and amplify vascular permeability. IL31, often elevated in chronic itch disorders, directly enhances pruritus by acting on cutaneous sensory neurons. IL4 and IL13 promote Th2 skewed immune responses, fostering a proallergic environment. Tryptase and histamine released from mast cells sensitize peripheral nerve endings, while nerve growth factor (NGF) supports neuronal hyperplasia and increases neuropeptide release. Collectively, these mediators form a complex signaling network bridging immune and neuronal pathways, perpetuating chronic inflammation and pruritus in CSU.

Mast cell–neuron and gut–brain–skin cross-talk

Mast cells and sensory neurons communicate bidirectionally through neuropeptides, cytokines, and receptors, creating a selfperpetuating inflammatory loop that sustains CSU symptoms. Neuronal release of SP, CGRP, and other mediators directly activates mast cells, while mast cell products such as histamine and tryptase sensitize peripheral nerves. In addition, the gut microbiota influences systemic immune responses and neuroendocrine pathways, forming a gut–brain–skin axis that modulates inflammation, pruritus perception, and treatment response in CSU.^[14,15]

Histological studies of urticarial lesions have revealed increased proximity of mast cells to nerve fibers and overexpression of neuropeptide receptors in affected skin.^[16]

Stress as a trigger and amplifier

Psychological stress is a well-established trigger and exacerbating factor in CSU. Stressful life events precede the onset or worsening of symptoms in up to 50% of patients.^[17] Mechanistically, the hypothalamic–pituitary–adrenal axis plays a pivotal role in the neuroendocrine stress response, primarily through the secretion of CRH and subsequent production of cortisol. Concurrently, the sympathetic–adrenal–medullary axis mediates the rapid autonomic response by releasing catecholamines, specifically norepinephrine and epinephrine. Together, these systems orchestrate a coordinated physiological adaptation to stressors, influencing numerous central and peripheral processes relevant to neural function and systemic homeostasis.

These stress mediators also impact immune function, skin barrier integrity, and neuropeptide expression.^[5]

CRH and mast cells

CRH, released both systemically and locally in the skin, can directly activate mast cells. CRH receptor 1 is expressed on dermal mast cells and keratinocytes. CRH-mediated mast cell activation has been implicated in both neurogenic inflammation and psychodermatoses [Figure 2].^[6]

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Figure 2:

A diagram depicting the role of neurogenic inflammation in chronic spontaneous urticaria. CGRP:Calcitonin Gene-Related Peptide.

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Functional neuroimaging

Neuroimaging studies in patients with CSU have consistently demonstrated altered functional activation within key brain regions implicated in the modulation of sensory and affective processing. Notably, aberrant activity has been observed in the anterior cingulate cortex, insular cortex, and amygdala. These findings suggest a dysregulated neural network potentially underlying the heightened pruritic perception and emotional distress associated with CSU, thereby providing a neurobiological substrate that may inform targeted therapeutic interventions.

These areas are involved in itch, stress, and emotion processing, supporting the CNS’s role in modulating urticaria severity.^[14]

Central sensitization

Sustained peripheral input leads to increased excitability of spinal and supraspinal neurons. Functional changes in pruritus-processing pathways, including glutamate receptor upregulation and altered inhibitory circuits, result in chronic itch perception independent of skin lesions.^[18]

NK1R antagonists

Aprepitant and serlopitant, initially developed as antiemetics, have shown benefit in chronic pruritus through NK1R blockade. Trials in CSU patients show modest but significant pruritus reduction.^[6]

Botulinum toxin

By inhibiting acetylcholine and neuropeptide release, intradermal botulinum toxin reduces pruritus and wheal formation in localized urticaria and cholinergic urticaria.^[17]

Stress management

CBT, relaxation training, and mindfulness have demonstrated efficacy in reducing urticaria flares, improving quality of life, and reducing antihistamine use.^[11]

Targeting TRP channels

TRPV1 and Transient Receptor Potential Ankyrin 1 (TRPA1) channels on sensory nerves mediate neuropeptide release and pruritus. Antagonists of these channels are under investigation for chronic itch disorders.^[9]

Biomarkers

Quantification of SP, CGRP, and NGF levels in both skin tissue and serum represents a promising approach for the identification of diagnostic and prognostic biomarkers in neuroinflammatory and neuropathic conditions. Furthermore, advanced imaging techniques that elucidate the spatial relationship between mast cells and nerve fibers provide critical insights into the pathophysiological mechanisms underpinning neuroimmune interactions. The assessment of mast cell–nerve proximity through high-resolution microscopy may augment the interpretative value of neuropeptide quantification, thereby enhancing the accuracy of disease characterization and informing therapeutic decision-making.

Personalized medicine

Using neuropsychological profiling to predict treatment response with special concern for genetic polymorphisms in NK1R or TRP channels.

Novel therapies

Include dual H1/NK1R antagonists, CRH receptor antagonists, and gut–brain–skin axis modulators.