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Neurogenic inflammation

MedicalCondition Medical Condition

Neurogenic inflammation is the mechanism that explains why is not just an immune event – it is also a neural event, driven by the same sensory fibres that carry pain and itch signals but operating through a local effector function that is entirely separate from their signalling to the central nervous system. When cutaneous C-fibres and Aδ-fibres are activated – by heat, KLK proteases, , , IL-31, or mechanical trauma – they do not only send a signal to the spinal cord and brain. They simultaneously release at their peripheral terminals, in the , where those neuropeptides act directly on blood vessels, , , and immune cells. The skin does not wait for the brain to respond to a signal before beginning its inflammatory response. It begins at the nerve ending itself.

That peripheral effector function – the local release of , CGRP, VIP, and neurotrophin signalling through NGF/TrkA – is neurogenic inflammation. In healthy skin it contributes to rapid vasodilation at injury sites, wound healing keratinocyte recruitment, and the antimicrobial environment of the acute immune response. In , excess -driven TSLP and direct TRPV1 activation by heat and Demodex proteases sustains neuropeptide release that drives the flushing, persistent erythema, and telangiectasia. In , IL-31 and TSLP maintain sensory neuron sensitisation that produces itch through TRPA1/TRPV3/IL-31RA pathways that operate independently of IgE and histamine – explaining why antihistamines are often ineffective in AD itch. In both conditions, each inflammatory episode sensitises neurons further through NGF/TrkA upregulation, lowering the threshold for the next episode. The condition teaches the nervous system to be more reactive with every flare.

The discovery that peripheral sensory neurons are not passive reporters of tissue damage but active participants in the inflammatory process itself – capable of releasing immunomodulatory locally and shaping the immune response at the skin surface – fundamentally changed the conceptual framework of dermatological inflammation. The consequence is a bidirectional system where the immune environment activates neurons, and neurons shape the immune environment, in a loop that neither the immune system nor the nervous system can resolve independently once it is established. [2]

The anatomical basis: sensory nerve distribution in skin

The skin is among the most densely innervated tissues in the body. Cutaneous sensory innervation arrives via unmyelinated C-fibres (slow-conducting, polymodal: responding to heat, chemical, and mechanical stimuli) and thinly myelinated Aδ-fibres (faster-conducting, primarily thermomechanical). These fibres terminate as free nerve endings in the – branching extensively through the and reaching into the – and as structured endings in the around blood vessels, sweat glands, and . [2]

This distribution is not incidental. The sensory fibres that release neuropeptides are positioned immediately adjacent to the keratinocytes whose differentiation and inflammatory signalling they influence, the mast cells whose degranulation they trigger, and the blood vessels whose tone they regulate. The communication is paracrine and direct – neuropeptide release at the nerve terminal acts on cells within nanometres of the release site, producing local tissue responses far faster than any systemic immune mediator could achieve. [14]

The primary neuropeptides

Substance P (SP). An 11- tachykinin neuropeptide stored in and released from dense-core vesicles in C-fibre terminals. SP acts on the neurokinin-1 receptor (NK-1R) expressed on mast cells, endothelial cells, keratinocytes, dendritic cells, and smooth muscle cells. Its primary vascular effects are vasodilation and plasma protein extravasation – the classic “wheal and flare” response. In mast cells, SP directly triggers degranulation through a non-IgE-mediated mechanism, releasing histamine, tryptase, prostaglandins, and VEGF. In keratinocytes, NK-1R activation drives -mediated cytokine production including IL-1β, , and IL-8. SP is degraded by neutral endopeptidase (neprilysin, NEP) – and importantly, Demodex mites produce proteases that inactivate NEP, reducing SP degradation and sustaining higher local SP concentrations in rosacea-affected skin. [12]

(CGRP). A 37-amino acid neuropeptide co-released with SP from C-fibre and Aδ-fibre terminals. CGRP acts on the CGRP receptor (CLR/RAMP1 heterodimer) expressed on dermal blood vessels, keratinocytes, dendritic cells, and Langerhans cells. Its primary vascular effect is potent vasodilation – more sustained than SP-mediated dilation because CGRP’s receptor binding triggers endothelial nitric oxide synthesis, producing prolonged vascular smooth muscle relaxation. CGRP inhibits Langerhans cell antigen presentation and suppresses Th1 cytokine production – creating an immune environment that favours Th2 responses in CGRP-rich tissue. In the 2024 Nature Communications rosacea study, hyperactivated CGRP+ sensory neurons were shown to drive γδ T cell-mediated IL-17A production, linking the neurogenic inflammation cascade directly to the Th17 inflammatory component of rosacea independent of the KLK5/ /mast cell route. [15]

CGRP also directly promotes keratinocyte proliferation – a 2024 study confirmed that CGRP released from sensory neurons drives keratinocyte proliferation through EGFR transactivation and downstream ERK1/2 signalling (in vitro tissue-engineering model; preliminary evidence). [9] The mechanism overlaps the LL-37-driven EGFR wound-healing pathway. In wound contexts, CGRP-driven keratinocyte proliferation is beneficial. In the context of chronic neurogenic inflammation – where CGRP is continuously elevated – it may contribute to the epidermal thickening and abnormal of chronically inflamed skin, though in vivo generalisation beyond the psoriasis model requires further study.

(VIP). Co-released with SP and CGRP from cutaneous sensory fibres. VIP acts on VPAC1 and VPAC2 receptors on mast cells, Langerhans cells, and T cells. Its primary immunological function is anti-inflammatory in the acute context – suppressing TNF-α, IL-12, and production and promoting regulatory T cell activity. However, VIP also promotes keratinocyte proliferation and lipid production – relevant in , where VIP-driven sebocyte stimulation contributes to excess and the comedogenic environment. VIP receptors are upregulated in atopic skin, suggesting the chronic neurogenic environment adapts by increasing VIP sensitivity, potentially shifting its acute anti-inflammatory function toward a pro-proliferative one. [2]

(NPY). Released from adrenergic sympathetic fibres rather than sensory C-fibres. NPY acts on Y1 and Y2 receptors on mast cells, dendritic cells, and keratinocytes, modulating mast cell degranulation (primarily inhibitory at low concentrations, potentially activating at higher doses) and promoting keratinocyte differentiation. NPY levels are reduced in atopic dermatitis lesional skin compared with healthy controls – a finding that may contribute to the mast cell disinhibition and impaired keratinocyte differentiation characteristic of AD skin. [2]

TRP channels – the sensory transducers

The Transient Receptor Potential (TRP) ion channels are the molecular sensors through which environmental and chemical stimuli activate the sensory neurons that produce neurogenic inflammation. In skin biology, four members are primary: [5]

TRPV1 ( receptor, heat threshold ~43°C). Expressed on C-fibres and Aδ-fibres innervating the epidermis and dermis, and on keratinocytes. Activated by heat, acidic pH, capsaicin, PAR2, and endocannabinoids. TRPV1 is the principal CGRP and SP release trigger in thermally- or chemically-activated neurogenic inflammation. In rosacea, TRPV1 expression is significantly elevated in – the upregulation driven by NGF (released by mast cells during degranulation), by repeated heat exposure, and by the Demodex-protease activation of PAR2 on TRPV1-expressing fibres. Each thermal trigger activates TRPV1 → SP/CGRP release → mast cell degranulation → further NGF → TRPV1 upregulation – the sensitisation cycle that makes rosacea progressively more reactive to temperature over time. [13]

TRPA1[3]

TRPV3 (warm temperature sensor, activated 31–39°C). Expressed abundantly on keratinocytes. TRPV3 activation drives TSLP release from keratinocytes – the mechanism established in the TSLP entity as the PAR2/keratinocyte-to-neuron itch bridge. TRPV3 gain-of-function mutations in the Olmsted syndrome produce severe palmoplantar keratoderma with intense pruritus and neurogenic skin inflammation – a genetic proof-of-concept for keratinocyte TRPV3 as a neurogenic itch driver analogous to the /KLK5 proof-of-concept for the protease regulation axis. [6]

TRPV4 (osmosensor, activated by mechanical stimuli and skin drying). TRPV4 on sensory neurons is activated by the osmotic stress of in barrier-disrupted skin, generating TSLP-mediated itch through the same TRPV4/TSLP/TRPA1 axis described in the TSLP entity. Notably, endothelin-1 (ET-1) – a vasoconstrictor peptide elevated in atopic lesional skin – activates TRPV4 through ETAR signalling, producing the neurogenic inflammation and pruritus associated with ET-1 dysregulation in AD and chronic barrier disorders. A 2025 Allergy study identified ET-1/ETAR as a neurogenic inflammation mediator causing and itch in atopic models – expanding the upstream activator set beyond the better-characterised KLK/PAR2/TSLP routes. [7]

NGF/TrkA – the sensitisation amplifier

Nerve Growth Factor (NGF) is the neurotrophin that determines the density, branching extent, and activation threshold of cutaneous sensory nerve fibres. In healthy skin, NGF is produced at homeostatic levels by keratinocytes and , maintaining the normal innervation density required for sensation and barrier monitoring. In inflamed skin – AD, rosacea, psoriasis, acne – multiple cell types dramatically upregulate NGF: mast cells (after IgE-mediated or SP-mediated degranulation), macrophages (after NF-κB activation), keratinocytes (after IL-1β and TNF-α stimulation), and eosinophils. [4]

NGF acts on its high-affinity receptor TrkA on C-fibre and Aδ-fibre terminals. TrkA activation does three things that are each clinically significant:

  1. TRPV1 upregulation. TrkA signalling increases TRPV1 gene expression and promotes TRPV1 trafficking to the plasma membrane of sensory terminals – more TRPV1 at the cell surface, lower activation threshold, more SP/CGRP released per thermal stimulus. This is the primary mechanism of heat sensitisation in chronic inflammatory skin disease.
  2. Nerve sprouting. NGF drives axonal growth and terminal branching – increasing the density of sensory nerve endings in chronically inflamed tissue. AD lesional skin contains significantly greater sensory nerve fibre density than non-lesional skin or healthy control skin. More nerve terminals per unit area means more neuropeptide release capacity per inflammatory stimulus.
  3. Mast cell recruitment and activation. NGF/TrkA signalling on mast cells promotes their migration to the inflamed site and enhances their degranulation response – a 2025 study confirming that NGF drives mast cell-specific TrkA signalling that amplifies local tissue inflammation. Released mast cell NGF then signals back to sensory neurons in a positive feedback loop: mast cell degranulation → NGF release → TrkA → TRPV1 upregulation → more SP/CGRP → more mast cell degranulation. [4]

The clinical consequence of the NGF/TrkA loop is neural sensitisation – a progressively lower activation threshold for neurogenic inflammation with each inflammatory episode. The nervous system in chronically inflamed skin is not just responding to ongoing stimulation; it has structurally adapted to the inflammatory environment by growing more nerve terminals, expressing more TRPV1, and maintaining a closer proximity between sensory terminals and mast cells than healthy skin maintains. This adaptation is not reversible on the timescale of clinical treatment – which is part of why established rosacea and chronic AD respond more slowly to anti-inflammatory treatment than recently developed presentations. [5]

IL-31 – the neuroimmune itch cytokine

IL-31 is the cytokine that most directly bridges the immune and neural components of itch – and its characterisation represents the most important recent advance in the mechanistic understanding of AD pruritus. It is produced primarily by Th2 cells and ILC2s in the atopic inflammatory environment, and it acts through the IL-31RA/OSMRβ heterodimeric receptor expressed on cutaneous sensory C-fibres, dorsal root ganglia neurons, keratinocytes, and immune cells. [10]

IL-31 signalling in sensory neurons activates JAK1/JAK2 → STAT3/STAT5 phosphorylation, downstream ERK1/2 activation, and ultimately direct action potential firing – producing itch through a mechanism entirely independent of histamine, IgE, and the classic H1 receptor pathway. This explains one of the most clinically consistent observations in AD management: antihistamines are largely ineffective for AD itch, despite being highly effective for urticaria and allergic rhinitis. The itch of AD is IL-31/JAK-STAT/neural rather than histamine/H1R/neural. [1]

IL-31 also acts on keratinocytes to: suppress , , and involucrin expression (compounding the Th2-driven barrier deficit); upregulate TSLP and production (amplifying the alarmin cascade); and stimulate NGF release (feeding back to the neural sensitisation loop). IL-31 is therefore not only an itch generator – it is a barrier disruptor and a neural sensitiser simultaneously. The three functions operate in parallel through the same receptor binding event. [16]

Nemolizumab – therapeutic validation of the IL-31/neural pathway.

Nemolizumab (Nemluvio, Galderma) is a humanised anti-IL-31RA monoclonal antibody – the first licensed treatment targeting the IL-31 pathway. In the UK, MHRA approval was granted in 2025 for moderate-to-severe atopic dermatitis in adults and adolescents aged 12 and over (≥30 kg bodyweight) in combination with topical corticosteroids and/or calcineurin inhibitors, and for moderate-to-severe prurigo nodularis in adults – both indications for patients who are candidates for systemic therapy. [8] NICE technology appraisal TA1077 (July 2025) subsequently recommended nemolizumab for NHS use in AD on those terms; NICE guidance for the prurigo nodularis indication is in development at the time of writing. The drug is also approved by the FDA and EMA. Its clinical profile directly validates the IL-31/neural itch mechanism: itch improvement begins at Day 2 of treatment – the fastest onset of itch response seen with any biologic in AD – consistent with a mechanism that is acting directly on sensory neuron signalling rather than upstream inflammatory processes requiring days to weeks to produce downstream effects.

The Day 2 onset is mechanistically informative. It rules out a purely immunological explanation (T cell modulation occurs over weeks) and confirms that nemolizumab is blocking IL-31 signalling in sensory neurons directly, producing neural desensitisation faster than any reduction in immune cell activity could achieve. [11]

Neurogenic inflammation across skin conditions

Rosacea. Neurogenic inflammation is arguably the dominant acute mechanism in ETR (Erythematotelangiectatic Rosacea) and contributes substantially to PPR (Papulopustular Rosacea). The specific pathway:

Demodex serine proteases activate PAR2 on TRPV1-expressing sensory fibres → SP/CGRP release → mast cell degranulation → histamine/ /NGF release → NGF upregulates TRPV1 → lower threshold for thermal/UV/spice TRPV1 activation on the next trigger exposure. The 2024 Nature Communications study added a new branch: hyperactivated CGRP+ sensory neurons drive γδ T cell IL-17A production → compounding the papulopustular inflammation through a neural route independent of the KLK5/LL-37/mast cell axis. [15]

Demodex inactivation of neutral endopeptidase (NEP) sustains SP at higher concentrations than normal skin maintains – effectively removing the molecule that degrades SP and prolonging the neurogenic vasodilation and mast cell activation that each flushing episode produces. This Demodex/NEP/SP mechanism explains why Demodex-targeted therapy (ivermectin, permethrin) produces clinical benefits in rosacea beyond their antiparasitic effect – reducing the SP-degradation inhibition that Demodex proteases provide. [12]

Atopic dermatitis. The itch of AD operates through at least three neurogenic routes simultaneously: TSLP/TRPV3/TRPA1 (keratinocyte-to-neuron via alarmin), IL-31/IL-31RA/JAK-STAT (direct immune cell-to-neuron cytokine signalling), and PAR2/SP/CGRP (protease-to-neuron via receptor activation). All three are operating in parallel in AD lesional skin. Antihistamines target none of these pathways – which is why the itch of AD remains antihistamine-resistant. [1]

The sensory nerve hyperinnervation of AD lesional skin – documented at significantly greater fibre density per unit area than healthy or non-lesional skin – is an NGF/TrkA-driven structural adaptation that represents the accumulated neural sensitisation of chronic inflammatory episodes. This hyperinnervation persists structurally beyond the acute inflammation, providing a physical explanation for why AD itch can remain severe even when lesional activity is controlled. [16]

Wound healing. At acute wound sites, neurogenic inflammation is beneficial and essential. SP promotes vasodilation providing the increased blood supply that healing tissue needs, drives mast cell degranulation releasing VEGF for angiogenesis, and activates keratinocyte proliferation through NK-1R. CGRP provides sustained vasodilation and promotes keratinocyte migration. NGF drives nerve re-ingrowth into the healing tissue that is required for normal wound closure. The neuropeptides present at wound sites are operating the same mechanism – but in the controlled context of acute injury rather than chronic dysregulation. [14]

Published

Clinical Application

Neurogenic inflammation does not have a single clinical management category – its involvement spans multiple conditions and requires condition-specific framing. What it provides across all of them is a mechanistic explanation for observations that are clinically familiar but often inadequately explained to clients: why rosacea flushing worsens with each untreated episode; why AD itch resists antihistamines; why stress reliably triggers both conditions; why sensitised skin becomes more sensitive over time rather than adapting. The nervous system is involved in all of these – not as a passive recipient of inflammatory signals but as an active co-driver.

Rosacea – what progressive sensitisation means for treatment

The TRPV1/NGF/TrkA sensitisation loop is the most clinically actionable implication of the neurogenic inflammation framework for rosacea clients. Every inadequately managed flushing episode contributes to a lower TRPV1 activation threshold for the next episode – the trigger list grows, the severity increases, and the skin becomes progressively more reactive not despite treatment but between treatments. This is not a complication of rosacea. It is the expected trajectory of a condition with a neural sensitisation mechanism at its core, and framing it that way changes the clinical conversation entirely.

Clients already prescribed ivermectin by their GP or dermatologist will often have noticed their skin becoming less reactive to triggers over the course of their treatment – and may be confused about why an antiparasitic cream is having what feels like a broader calming effect on their sensitivity. The Demodex/NEP/SP mechanism explains exactly this. Reducing Demodex burden restores neutral endopeptidase function, which accelerates SP clearance at nerve terminals – less Substance P sustained per trigger, less mast cell activation, less neurogenic vasodilation per flushing episode. The drug is doing more than its antiparasitic label suggests. Being able to explain that to a client – connecting the prescription they are already on to the mechanism driving their sensitivity – is a meaningful clinical communication that reinforces both the prescription compliance and their engagement with the broader treatment programme.

Clients presenting on brimonidine gel (Mirvaso, a UK prescription medicine for facial erythema) will typically describe good initial erythema control with a tendency for rebound redness after the effect wears off. The vasoconstriction mechanism and its rebound profile make sense in the neurogenic context: brimonidine is pharmacologically restoring the vasoconstriction that healthy sympathetic NPY tone provides, in skin where the SP/CGRP vasodilatory drive has substantially outweighed it – but it is not addressing the underlying neurogenic imbalance. That explanation is clinically useful precisely because it sets realistic expectations: brimonidine controls a symptom; reducing the neurogenic load through consistent treatment addresses the cause. For procedure planning, one safety point is non-negotiable – the MHRA 2017 Drug Safety Update contraindicates brimonidine on damaged skin. Any client using brimonidine for rosacea who is undergoing , thulium laser resurfacing, or a deep chemical peel must pause application at the treatment site during the barrier disruption and re-epithelialisation window. Raising this as a pre-procedure instruction – not as prescribing advice, but as a practical timing conversation – is within scope and clinically important.

in neurogenic rosacea. CAP’s -mediated effects include reduction of TRPV1 expression at the tissue level – the same mechanism through which some topical antioxidant formulations ( , derivatives, ) reduce TRPV1-mediated sensitivity in rosacea. Reducing NF-κB activation with CAP simultaneously reduces NGF production in keratinocytes and mast cells – slowing the neural sensitisation loop at its amplification step. This is a legitimate, if indirect, anti-neurogenic mechanism of CAP in rosacea that sits alongside its cytokine-suppressive and antimicrobial properties. Clients on a CAP course for rosacea who report that their skin is becoming less trigger-reactive between sessions are noticing a real effect. That is the neurogenic sensitisation loop decelerating.

GABA topicals. A 2025 PMC review identified topical GABA receptor agonism as a neurogenic modulation strategy relevant to rosacea – GABA receptors on cutaneous sensory terminals act as inhibitory signals that raise the SP/CGRP release threshold. Topical GABA-based formulations are increasingly present in rosacea-specific cosmeceutical lines on this basis. Mechanistic rationale is solid; robust clinical trial data is limited at the time of writing. Appropriate framing for a client asking about a GABA-containing product: mechanistically plausible, part of a credible and growing research direction, not yet substantiated at RCT level.

Atopic dermatitis – the antihistamine-resistance explanation

The IL-31/JAK-STAT/neural itch mechanism is the direct explanation for antihistamine resistance in AD. When a parent has given their child antihistamine every night for months without itch improvement, the explanation is precise and genuinely useful: the itch in eczema uses a completely different pathway to the itch in allergies. Antihistamines block H1 receptors. AD itch operates through IL-31 acting directly on sensory neurons via JAK1/JAK2 → STAT3 signalling – entirely independent of histamine, IgE, and the H1 receptor. The drug is blocking the wrong channel entirely. That explanation resolves a confusion that may have been undermining trust in every management recommendation, and it does so with a mechanism the client can hold onto.

Nemolizumab – context for client conversations. Nemolizumab (Nemluvio, MHRA-approved February 2025, recommended on the NHS by NICE TA1077 July 2025) is the biologic that directly targets IL-31RA – blocking the cytokine pathway that acts on sensory neurons to produce itch. Its Day 2 itch response is faster than dupilumab’s two-to-four week itch improvement timeline because it is acting on the sensory neuron directly, not on the upstream immune environment whose resolution produces downstream itch benefit as a secondary effect. Dupilumab addresses the Th2 immune environment; nemolizumab addresses the neural itch signal. They operate on different parts of the same problem. If a client or parent raises nemolizumab – or if a client’s AD itch is disproportionate to their skin severity and not improving despite apparently effective treatment – the appropriate response is to acknowledge the mechanism clearly and suggest the conversation belongs with their GP or dermatologist, who can assess eligibility under the NICE criteria. That is the extent of the clinic’s role with this drug. Awareness of the mechanism; clarity about the referral pathway; confidence in the conversation.

The neural hyperinnervation expectation-management point. AD skin with significant lesional history has a structurally greater sensory nerve fibre density than healthy skin, driven by accumulated NGF/TrkA-mediated nerve sprouting over multiple inflammatory episodes. Reducing itch through professional treatment removes the ongoing stimulus for further sensitisation – but the existing hyperinnervation does not immediately regress. Itch in successfully managed AD may persist at lower intensity not because treatment is failing but because the nervous system has more itch-capable fibres than healthy skin contains, and those fibres remain sensitised by the TRPV1 upregulation and TRP channel overexpression that accumulated during the active disease period. This is a clinical expectation-setting point with real consequences for treatment adherence. Clients who understand why their itch persists even when their skin looks significantly better are less likely to discontinue effective treatment. The explanation – neural memory, structural adaptation, gradual desensitisation – is the same framing used in the PAR2 entity, and applies with equal force here.

Post-procedure neurogenic considerations

Any procedure generating significant barrier disruption – thulium laser resurfacing, RF microneedling, deep chemical peel – activates the sensory fibres whose neuropeptide release drives neurogenic inflammation at the wound site. In healthy skin this is beneficial and necessary: SP and CGRP vasodilation, mast cell degranulation supporting VEGF and angiogenesis, NGF supporting nerve re-ingrowth into healing tissue. In clients with pre-existing neurogenic sensitisation – rosacea, chronic AD, significant Demodex burden – the same stimulus produces a disproportionate neurogenic response that exceeds the wound-healing contribution and moves into inflammatory amplification territory.

Pre-procedural preparation in sensitised clients addresses this directly. optimisation in the two to four weeks before a stimulatory procedure reduces KLK5-driven PAR2/TSLP neural activation at the barrier – lowering the neurogenic baseline from which the procedure’s SP/CGRP surge launches. optimisation maximises expression at the wound site, reducing microbial PAR2 activation during the barrier-open window. For clients currently on a prescribed ivermectin course, completing that course before scheduling a stimulatory procedure is worth raising as a timing consideration: restored NEP function means the procedure-induced SP surge clears faster, the mast cell activation per unit of SP released is lower, and the post-procedure inflammatory response is less likely to cross into the disproportionate neurogenic territory that sensitised skin is vulnerable to. This is a scheduling conversation with the client, not a prescribing decision – but it is a genuinely meaningful one for procedure outcomes.

The post-procedure period has its own neurogenic consideration beyond infection risk. Clients returning after treatment and reporting that their skin feels “constantly activated” – warm without visible erythema, reactive to products that previously had no effect – are typically describing the acute neurogenic inflammation that stimulatory procedures trigger, operating in skin that already had an elevated neurogenic baseline. Managing expectations before the procedure – telling clients this is a normal transient response, naming its mechanism, giving a realistic resolution timeline – converts a potential concern about treatment failure into a predictable and understood part of the process.

References

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  2. Choi JE, Di Nardo A (2018). Skin neurogenic inflammation. Semin Immunopathol, 40(3), 249-259 .

  3. Feng J, Yang P, Mack MR, et al. (2017). Sensory TRP channels contribute differentially to skin inflammation and persistent itch. Nat Commun, 8(1), 980 .

  4. Jiang T, Ao X, Xiang X, et al. (2024). Mast cell activation by NGF drives the formation of trauma-induced heterotopic ossification. JCI Insight, 10(1) .

  5. Lee SG, Kim J, Lee YI, et al. (2023). Cutaneous neurogenic inflammation mediated by TRPV1-NGF-TRKA pathway activation in rosacea is exacerbated by the presence of Demodex mites. J Eur Acad Dermatol Venereol, 37(12), 2589-2600 .

  6. Lee WJ, Shim WS (2021). Cutaneous Neuroimmune Interactions of TSLP and TRPV4 Play Pivotal Roles in Dry Skin-Induced Pruritus. Front Immunol, 12, 772941 .

  7. Leo R, Jochebeth A, Abdulrahman N, et al. (2026). The Neurogenic Inflammation Mediator Endothelin-1 Causes Human Skin Barrier Disruption in Atopic Dermatitis via an ETAR/TRPA1-Axis. Allergy, 81(3), 818-829 .

  8. Medicines and Healthcare products Regulatory Agency (2025). Nemolizumab approved to treat prurigo nodularis and atopic dermatitis (eczema) for patients in the UK.

  9. Pepin R, Ringuet J, Beaudet MJ, et al. (2024). Sensory neurons increase keratinocyte proliferation through CGRP release in a tissue engineered in vitro model of innervation in psoriasis. Acta Biomater, 182, 1-13 .

  10. Shanshal M, Uthayakumar A (2026). Nemolizumab for chronic pruritus beyond atopic dermatitis and prurigo nodularis: a systematic review and synthesis of emerging evidence. J Dermatolog Treat, 37(1), 2612882 .

  11. Ständer S, Elmariah SB, Kwatra SG, et al. (2025). Rapid improvement of itch with nemolizumab in atopic dermatitis and prurigo nodularis phase 3 studies. J Eur Acad Dermatol Venereol .

  12. Wang H, Zhou C (2025). Advances in the pathogenesis of rosacea. Front Immunol, 16, 1705588 .

  13. Xiao T, Sun M, Zhao C, et al. (2023). TRPV1: A promising therapeutic target for skin aging and inflammatory skin diseases. Front Pharmacol, 14, 1037925 .

  14. Xing L, Chen B, Qin Y, et al. (2024). The role of neuropeptides in cutaneous wound healing: a focus on mechanisms and neuropeptide-derived treatments. Front Bioeng Biotechnol, 12, 1494865 .

  15. Zhang Y, Li T, Zhao H, et al. (2024). High-sensitive sensory neurons exacerbate rosacea-like dermatitis in mice by activating γδ T cells directly. Nat Commun, 15(1), 7265 .

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