VITAMIN D AND NEUROGENIC INFLAMMATION: WHAT’S THE CONNECTION?

Psoriasis and atopic dermatitis are usually discussed in terms of immune dysfunction and epidermal barrier function. Yet both conditions also have a pronounced neurogenic component. Sensory nerve fibers in the skin release neuropeptides, including substance P (SP) and calcitonin gene-related peptide (CGRP). These signaling molecules can dilate blood vessels, promote pro-inflammatory cytokine production, and recruit immune cells. Clinically, this may manifest as itch, redness, swelling, and flushing [1, 2]. Vitamin D has long been associated with both conditions, but the mechanisms behind this relationship are not fully understood.

Researchers at Weill Cornell Medicine in New York, USA, prepared a narrative review examining vitamin D from the perspective of the peripheral sensory nervous system and considering the skin as an integrated neuroimmune-endocrine organ [1]. The paper is not a clinical trial or a systematic review. The authors bring together findings from cell experiments, animal studies, computational modeling, and a small number of clinical observations to develop a conceptual hypothesis.

The skin as a vitamin D factory

The skin is the only organ that can produce and activate vitamin D on its own. The process unfolds in stages under ultraviolet B (UVB) radiation (290–320 nm).

In the classical pathway, UVB rays act on the epidermis, where the precursor molecule 7-dehydrocholesterol (7-DHC) is converted first into previtamin D3 and then into vitamin D3. Vitamin D3 is not yet active; it must undergo two successive enzymatic steps.

The first step is carried out by 25-hydroxylase (CYP2R1), found mainly in the liver but also in skin cells. It converts vitamin D3 into the intermediate transport form 25-hydroxyvitamin D3 [25(OH)D3].
The second, key step is performed by 1-alpha-hydroxylase (CYP27B1). It adds another hydroxyl group, producing the hormonally active form 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], also known as calcitriol.

Skin keratinocytes express both enzymes, allowing them to complete activation locally rather than relying entirely on metabolic signals from the liver and kidneys.

Alongside the classical pathway, the authors describe an alternative route involving the enzyme CYP11A1, also known as cholesterol side-chain cleavage enzyme. This pathway produces biologically active derivatives of lumisterol and tachysterol, as well as vitamin D analogs. These metabolites interact not only with the classical vitamin D receptor (VDR), but also with other intracellular targets, including retinoic acid receptors and liver X receptors. The authors describe these effects as anti-inflammatory and cell-differentiating.

The review highlights an important paradox: UVB radiation can stimulate opposing signaling pathways at the same time. In addition to triggering vitamin D production, UVB stimulates nerve growth factor (NGF) synthesis and the release of the neuropeptides CGRP and SP in tissues. In other words, the same external stimulus can activate both anti-inflammatory endocrine pathways and neurogenic inflammatory cascades. The balance between these responses helps shape how the skin reacts.

How might vitamin D act on sensory neurons?

The review’s central hypothesis is that vitamin D may act directly on peripheral sensory nerves in the skin and, in doing so, modulate neurogenic inflammation. The proposed sequence is that active vitamin D metabolites bind to receptors on neurons, alter the synthesis or release of inflammatory mediators, and ultimately reduce redness, swelling, and itch.

One anatomical basis for this hypothesis is the detection of nuclear vitamin D receptors (VDR) in the cell bodies of sensory neurons in the dorsal root ganglia (DRG). The neurons’ extensions innervate the dermis and epidermis, where they help detect pain, itch, and temperature. The presence of VDR suggests that sensory neurons may be capable of responding to vitamin D signals.

However, experimental findings on what happens after this stimulation are mixed. It is important to distinguish the level at which an effect was studied:

Mediator synthesis. In a culture of human thyroid cells, vitamin D reduced the expression of messenger RNA (mRNA) for CGRP, a key pro-inflammatory neuropeptide. In a rat study, however, a synthetic vitamin D analog increased CGRP and SP in the sciatic nerve, apparently through NGF.
Release from cells. In preliminary laboratory findings from the review’s authors, vitamin D metabolites dose-dependently reduced CGRP and interleukin-6 (IL-6) release in a culture of mouse DRG neurons.
Blood concentration. There are no dermatology data on systemic levels of these substances. Indirect clinical evidence comes from neurology: a secondary analysis of a randomized trial in people with episodic migraine found that daily vitamin D supplementation at 2,000 IU for 12 weeks was associated with a statistically significant decrease in serum CGRP levels between migraine attacks.

The researchers also focused on the capsaicin receptor, the TRPV1 ion channel, which plays an important role in sensations of burning and itch. In tests conducted outside a living organism, using embryonic kidney cells, and in molecular modeling, the metabolite 25(OH)D3 behaved as a partial agonist of this channel. On its own, it produced only a small inward calcium current; however, at high capsaicin concentrations, it reduced the excessive current through the receptor [4].

Taken together, the findings suggest that vitamin D may modulate several parts of the neurogenic response: it may interact with VDR, influence the synthesis and release of neuropeptides, and affect ion channels involved in itch and pain. But this remains a working hypothesis that needs to be tested in clinical studies involving human skin.

Psoriasis and atopic dermatitis: the neurogenic component and the role of vitamin D

Although psoriasis and atopic dermatitis differ in their immunological profiles and clinical presentation, both have a pronounced neurogenic component. In affected skin, peripheral sensory nerves do more than passively transmit pain and itch signals: by releasing neuropeptides into the tissue, they can actively contribute to inflammatory cascades. The authors consider these mechanisms alongside what is known about vitamin D in each condition.

Psoriasis: the IL-23/IL-17 axis and sensory nerves

Mouse models show that sensory nerve fibers can use CGRP to stimulate epidermal dendritic cells, known as Langerhans cells, to produce interleukin-23 (IL-23). This cytokine, in turn, promotes IL-17A and IL-22 production, key mediators of psoriatic inflammation. Further evidence for a role of the nervous system comes from studies in which lidocaine, a local anesthetic, reduced psoriasis-like inflammation in animals. In a small clinical observation, epidural lidocaine was followed by regression of plaques in four patients [5].

Meta-analyses have found a statistically significant association between lower serum vitamin D levels and more severe psoriasis, although a cause-and-effect relationship has not been established. Topical medications containing synthetic vitamin D derivatives, including calcipotriol and calcitriol, have been used in dermatology since 1985. Their effects are traditionally linked to reduced keratinocyte proliferation and normalized differentiation. The authors raise another possibility: some of the effects of topical vitamin D derivatives may result from locally suppressing CGRP release from sensory nerve endings in psoriatic plaques.

Atopic dermatitis: the itch–inflammation cycle

Atopic dermatitis is associated with increased innervation of the epidermis and dermis during flares. The density of fine nerve fibers containing SP and CGRP is substantially higher in affected areas. In addition, DRG sensory neurons have been found to co-express receptors for interleukin-31 (IL-31), a major itch-promoting cytokine, and TRPV1 ion channels. This may help link itch, scratching, and inflammation in a self-reinforcing cycle.

The relationship between vitamin D and atopic dermatitis remains unclear. Many studies report vitamin D deficiency or insufficiency in affected patients, and some clinical studies have found a reduction in dermatitis severity scores following supplementation. Other studies, however, have found no association between blood 25(OH)D levels and symptom severity, and no benefit from oral supplementation. The authors emphasize that convincing evidence of a direct cause-and-effect relationship is lacking. Further study is needed to clarify how vitamin D metabolites may affect neurogenic itch and skin-barrier function.

Practical takeaways and therapeutic perspectives

The review does not offer a treatment protocol: it provides no specific doses, recommendations for topical products, or procedural guidance. The findings also warrant caution. This is a narrative review; most mechanistic evidence comes from cell and animal studies, and the role of vitamin D in several pathways—including those involving SP—remains unexplored.

For clinicians and skincare practitioners, the value of the review lies in its perspective. Clinicians and skincare practitioners often attribute persistent itch, burning, widespread redness, and vascular reactivity in psoriasis and atopic dermatitis solely to immune inflammation or a compromised skin barrier. The authors’ model highlights that overactive sensory nerve fibers may also contribute directly to these symptoms.

This perspective may help practitioners better understand patients’ complaints, explain possible sources of sensory discomfort, and support coordinated care with a dermatologist. If clinical trials confirm this hypothesis, regulating CGRP release and modulating TRPV1 activity through vitamin D metabolites could address both the immune and neurogenic components of these skin conditions.