Neuronal Regulation of Inflammation in Atopic Dermatitis.

Atopic dermatitis is a common chronic pruritic inflammatory disease of the skin involving neuro-immune communication. Neuronal mechanism-based therapeutic treatments remain lacking. We investigated the efficacy of intravenous lidocaine therapy on atopic dermatitis and the underlying neuro-immune mechanism. Pharmacological intervention, immunofluorescence, RNA-sequencing, genetic modification and immunoassay were performed to dissect the neuro-immune basis of itch and inflammation in atopic dermatitis-like mouse model and in patients. Lidocaine alleviated skin lesions and itch in both atopic dermatitis patients and calcipotriol (MC903)-induced atopic dermatitis model by blocking subpopulation of sensory neurons. QX-314, a charged NaV blocker that enters through pathologically activated large-pore ion channels and selectivity inhibits a subpopulation of sensory neurons, has the same effects as lidocaine in atopic dermatitis model. Genetic silencing NaV 1.8-expressing sensory neurons was sufficient to restrict cutaneous inflammation and itch in the atopic dermatitis model. However, pharmacological blockade of TRPV1-positive nociceptors only abolished persistent itch but did not affect skin inflammation in the atopic dermatitis model, indicating a difference between sensory neuronal modulation of skin inflammation and itch. Inhibition of activity-dependent release of calcitonin gene-related peptide (CGRP) from sensory neurons by lidocaine largely accounts for the therapeutic effect of lidocaine in the atopic dermatitis model. NaV 1.8+ sensory neurons play a critical role in pathogenesis of atopic dermatitis and lidocaine is a potential anti-inflammatory and anti-pruritic agent for atopic dermatitis. A dissociable difference for sensory neuronal modulation of skin inflammation and itch contributes to further understanding of pathogenesis in atopic dermatitis.

Atopy patch testing--a diagnostic tool?

Atopic dermatitis (AD) is a relapsing inflammatory skin disease often associated with intractable chronic itch. The sensation of itch depends on the activity of pruriceptive sensory neurons whose nerve fibers innervate the dermis and epidermis. These fibers can respond to factors secreted by keratinocytes (e.g., thymic stromal lymphopoietin) and immune cells (e.g., IL-31, histamine, and proteases) (1). However, the pathogenesis of chronic itch and inflammation in AD is not well understood, and therapeutic options are limited. In PNAS, Emrick et al. (2) perform an elegant study in which they determine the cellular and molecular mechanisms by which the AD-associated gene Tmem79 drives skin inflammation and itch. Emrick et al. find that TMEM79 acts as a putative glutathione transferase to decrease oxidative stress in keratinocytes to prevent mast cell activation and histamine-driven neuronal activation and itch (Fig. 1). This study is an important advance in our understanding of the molecular and cellular mechanisms of AD. Fig. 1. Tmem79 reduces oxidative stress to protect against itch and AD. Tmem79 , a gene linked to AD, is expressed in keratinocytes and sensory neurons. Emrick et al. (2) find that loss of Tmem79 causes an increase in RS in keratinocytes and the induction of PGE2 levels. PGE2 acts through EP3 receptors to recruit dermal mast cells. Mast cell degranulation results in the release of histamine, which acts on H1R and H4R expressed by C-fiber sensory neurons to drive itch. Potential strategies to inhibit itch in AD suggested by this study include the use of antioxidants, EP3 receptor antagonists, and histamine receptor (H4R/H1R) antagonists. AD affects ∼20% of children in the developed world and 2 to 8% of adults, with 87 to 100% of these patients experiencing chronic itch (3, 4). It is generally thought that AD is caused by a combination of skin … [↵][1]1To whom correspondence should be addressed. Email: isaac_chiu{at}hms.harvard.edu. [1]: #xref-corresp-1-1

Peroxisome proliferator-activated receptor α regulates skin inflammation and humoral response in atopic dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disease marked by impaired barrier function and immune dysregulation. This study explores transcriptomic differences between lesional (IL) and perilesional (PL) skin in patients with AD, focusing on barrier-related and vitamin D-associated pathways. RNA sequencing was performed on matched IL and PL biopsies from 21 adults with moderate-to-severe AD. Differential gene expression, pathway enrichment, and correlation analysis with clinical variables were assessed. A total of 8817 genes were differentially expressed in IL versus PL skin (padj < 0.05). Among genes with the highest level of dysregulation, strong upregulation was observed for inflammatory mediators (IL-19, IL-8, CXCL6), and epidermal remodeling and barrier-disrupting genes (MMP1, GJB2). The vitamin D pathway genes CYP27B1 and CYP24A1 were also significantly upregulated. In contrast, key barrier-related genes such as FLG2 and CGNL1 were markedly downregulated. While some patterns in gene expression showed subgroup-specific trends, no independent clinical predictors emerged in multivariate models. Reactome pathway analysis revealed the enrichment of pathways involved in keratinization, cornified envelope formation, IL-4/IL-13 signaling, chemokine activity, and antimicrobial responses, highlighting coordinated structural and immunologic dysregulation in lesional skin. Lesional skin in AD displays a distinct transcriptomic profile marked by barrier impairment, heightened inflammatory signaling, and activation of vitamin D-related pathways. These findings provide the first RNA-seq-based comparison of IL and adjacent PL skin in AD. We identify subclinical activation in PL skin and vitamin D pathway upregulation with disrupted gene coordination in lesions. These findings enhance our understanding of the molecular mechanisms underlying inflammation in AD.

Biologic therapies are increasingly used to treat chronic inflammatory skin diseases such as psoriasis and atopic dermatitis. In clinical practice, scores based on evaluation of objective and subjective symptoms are used to assess disease severity, leading to evaluation of treatment goals with clinical decisions on treatment initiation, switch to another treatment modality or to discontinue current treatment. However, this visual-based scoring is relatively subjective and inaccurate due to inter- and intraobserver reliability. Optical coherence tomography (OCT) is a fast, high-resolution, in vivo imaging modality that enables the visualization of skin structure and vasculature. We evaluated the use of OCT for quantification and monitoring of skin inflammation to improve objective assessment of disease activity in patients with psoriasis and atopic dermatitis. We assessed the following imaging parameters including epidermal thickness, vascular density, plexus depth, vessel diameter, and vessel count. A total of four patients with psoriasis or atopic dermatitis were treated with biologic agents according to current treatment guidelines. OCT was used to monitor their individual treatment response in a target lesion representing disease activity for 52 weeks. Psoriatic and eczema lesions exhibited higher epidermal thickness, increased vascular density, and higher vessel count compared to uninvolved skin. An upward shift of the superficial vascular plexus accompanied by smaller vessel diameters was seen in psoriasis in contrast to atopic dermatitis, where larger vessels were observed. A response to biologic therapy was characterized by normalization of the imaging parameters in the target lesions in comparison to uninvolved skin during the observation period of 52 weeks. Optical coherence tomography potentially serves as an instrument to monitor biologic therapy in inflammatory skin diseases. Imaging parameters may enable objective quantification of inflammation in psoriasis or atopic dermatitis in selected representative skin areas. OCT may reveal persistent subclinical inflammation in atopic dermatitis beyond clinical remission.

Epidemiological evidence suggests that particulate matter (PM) exposure can trigger or worsen atopic dermatitis (AD); however, the underlying mechanisms remain unclear. Recently, pregnane X receptor (PXR), a xenobiotic receptor, was reported to be related to skin inflammation in AD. This study aimed to explore the effects of PM on AD and investigate the role of PXR in PM-exposed AD. In vivo and in vitro AD-like models were employed, using BALB/c mice, immortalized human keratinocytes (HaCaT), and mouse CD4 + T cells. Topical application of PM significantly increased dermatitis score and skin thickness in AD-like mice. PM treatment increased the mRNA and protein levels of type 17 inflammatory mediators, including interleukin (IL)-17A, IL-23A, IL-1β, and IL-6, in AD-like mice and human keratinocytes. PM also activated PXR signaling, and PXR knockdown exacerbated PM-induced type 17 inflammation in human keratinocytes and mouse CD4 + T cells. In contrast, PXR activation by rifampicin (a human PXR agonist) reduced PM-induced type 17 inflammation. Mechanistically, PXR activation led to a pronounced inhibition of the nuclear factor kappa B (NF-κB) pathway. In summary, PM exposure induces type 17 inflammation and PXR activation in AD. PXR activation reduces PM-induced type 17 inflammation by suppressing the NF-κB signaling pathway. Thus, PXR represents a promising therapeutic target for controlling the PM-induced AD aggravation.

Atopic Dermatitis Is Associated with Dermatitis Herpetiformis and Celiac Disease in Children

Atopic dermatitis (AD) is a common chronic inflammatory skin condition characterised by pruritus and recurrent eczematous patches and plaques. It impacts sleep and its visibility can lead to stigmatisation, low self-esteem, social withdrawal, reduced quality of life (QOL), and psychological burden. This study explores the relationship between AD and mental health, including possible causation pathways. A literature review was conducted in PubMed without using limiters. AD carries higher odds of suicidality and an increased risk of depression, anxiety, alexithymia, and obsessive-compulsive disorder (OCD) across all severities. While some studies report an association of AD with attention deficit hyperactivity disorder (ADHD), and possibly autism spectrum disorder (ASD), others do not. There is increasing evidence that AD contributes to chronic low-grade inflammation and cognitive impairment (CI). Causative factors for mental health complications of AD likely include both psychosocial and biological variables. AD is associated with higher levels of cutaneous and circulating proinflammatory cytokines; these can breach the blood-brain barrier and trigger central nervous system events, including oxidative stress, neurotransmitter breakdown, altered serotonin metabolism, and reduced neurogenesis in several brain regions. Excessive inflammation in AD may thus contribute to CI, depression, and suicidality. AD providers should be vigilant about mental health.

Tralokinumab is a monoclonal antibody that specifically neutralizes interleukin (IL)-13, a key driver of skin inflammation and barrier abnormalities in atopic dermatitis (AD). This study evaluated early and 2-year impacts of IL-13 neutralization on skin and serum biomarkers following tralokinumab treatment in adults with moderate-to-severe AD. Skin biopsies and blood samples were evaluated from a subset of patients enrolled in the Phase 3 ECZTRA 1 (NCT03131648) and the long-term extension ECZTEND (NCT03587805) trials. Gene expression was assessed by RNA sequencing; protein expression was assessed by immunohistochemistry and immunoassay. Tralokinumab improved the transcriptomic profile of lesional skin by Week 4. Mean improvements in the expression of genes dysregulated in AD were 39% at Week 16 and 85% at 2 years with tralokinumab, with 15% worsening at Week 16 with placebo. At Week 16, tralokinumab significantly decreased type 2 serum biomarkers (CCL17/TARC, periostin, and IgE), reduced epidermal thickness versus placebo, and increased loricrin coverage versus baseline. Two years of tralokinumab treatment significantly reduced expression of genes in the Th2 (IL4R, IL31, CCL17, and CCL26), Th1 (IFNG), and Th17/Th22 (IL22, S100A7, S100A8, and S100A9) pathways as well as increased expression of epidermal differentiation and barrier genes (CLDN1 and LOR). Tralokinumab also shifted atherosclerosis signaling pathway genes (SELE, IL-37, and S100A8) toward non-lesional expression. Tralokinumab treatment improved epidermal pathology, reduced systemic markers of type 2 inflammation, and shifted expression of key AD biomarkers in skin towards non-lesional levels, further highlighting the key role of IL-13 in the pathogenesis of AD. NCT03131648, NCT03587805.

Bacterial infections and atopic dermatitis.

Mast cells (MCs) are immune cells residing in tissues and playing indispensable roles in maintaining homeostasis and inflammatory states. Skin lesions associated with atopic dermatitis (AD) and type 2 skin inflammation display an increment in MCs, which have both pro- and anti-inflammatory effects. The direct and indirect activations of skin MCs by environmental factors such as Staphylococcus aureus can instigate type 2 skin inflammation in AD with poorly understood mechanisms. Furthermore, both IgE-dependent and -independent degranulation of MCs contribute to pruritus in AD. Conversely, MCs suppress type 2 skin inflammation by promoting Treg expansion through IL-2 secretion in the spleen. Moreover, skin MCs can upregulate gene expression involved in skin barrier function, thus mitigating AD-like inflammation. These functional variances of MCs in AD could stem from differences in experimental systems, their localization, and origins. In this review, we will focus on how MCs are maintained in the skin under homeostatic and inflammatory conditions, and how they are involved in the pathogenesis of type 2 skin inflammation.

Nemolizumab is a monoclonal antibody directed against the interleukin-31 receptor A subunit, which is involved in the pathogenesis of pruritus and inflammation in atopic dermatitis (AD). Clinical trial results were combined with population PK (popPK) and pharmacokinetic/ pharmacodynamic (PK/PD) models to optimize nemolizumab dosing. Phase 1 and 2a clinical studies indicated that weight-based nemolizumab dosing reduced pruritus in patients with moderate-to-severe AD with good safety and tolerability even at the highest dose (3 mg/kg single dose and 2 mg/kg multiple doses). Nemolizumab PK profile was characterized by a slow absorption with peak serum concentrations reached 4.5-9.2 days post-dose, and a long terminal half-life ranging from 12.6 to 16.5 days. A change from weight-based dosing to flat dose was supported by an additional phase 2b study sponsored by Galderma. Flat dosing provides several practical advantages, including ease of preparation for self- or auto-injection and reduced chance of dosing errors. Doses of 10, 30, and 90 mg were selected based on popPK and PK/PD simulations to result in nemolizumab serum concentrations sufficient to achieve efficacy. Loading doses were administrated at the 2 lower doses in order to achieve target systemic concentrations from the first injection. The efficacy of Nemolizumab in improving cutaneous signs of inflammation and pruritus in AD and its safety profile, combined with popPK and PK/PD analyses, supported selection of the flat-dose regimen of 30 mg (with a 60 mg loading dose) given every 4 weeks subcutaneously for 16 weeks in the phase 3 ARCADIA studies sponsored by Galderma. J Drugs Dermatol. 2023;22(10):1017-1020 doi:10.36849/JDD.7437R1.

What's new in atopic dermatitis?

Atopic dermatitis is a chronic hereditary recurrent skin disease. One of the most pronounced symptoms of this dermatosis is itchy skin. Pruritus accompanies atopic dermatitis in more than 80% of cases. This review presents modern data on the mechanisms of pruritus formation in atopic dermatitis. The issues of etiological factors, neuroimmune interactions, peculiarities of skin dysfunction, as well as the role of stress are considered. The relevance of studying the topic is due to the high prevalence of atopic dermatitis among the population, a decrease in the quality of life and the lack of effective therapy. Analysis of the literature indicates the need for a comprehensive assessment of the pathogenetic mechanisms of the development of pruritus in atopic dermatitis. A more in-depth study of the mechanisms of neurogenic inflammation in atopic dermatitis will contribute to the development of new methods of diagnosis and treatment.