Dupilumab Inhibits Vascular Leakage of Blood Proteins Into Atopic Dermatitis Skin.

BACKGROUND: Atopic dermatitis (AD) skin lesions are associated with oozing, bleeding, and erythema. This suggests that AD is associated with vascular changes. Dupilumab is an antibody to the alpha subunit of IL-4 receptor that demonstrates strong efficacy in the treatment of AD. IL-4 is known to reduce the permeability barrier function of vascular endothelium. OBJECTIVE: To examine the effects of dupilumab on vascular barrier function in AD skin. METHODS: Using proteomic analysis, we evaluated the plasma protein composition in skin tapes of lesional and nonlesional skin of adults and adolescents with moderate to severe AD over the course of a 16-week treatment with dupilumab and compared those with matched healthy subjects. RESULTS: At baseline, 115 plasma proteins were detected in AD skin and globally increased (1.5-fold or greater) compared with healthy skin. Functionally, these proteins included immunoglobulins, proteins involved in the coagulation process, enzymes, protease inhibitors, transport proteins, acute-phase proteins, complement proteins, and other pleiotropic proteins. Noteworthy, fibrinogens, fibronectin, and heme-binding proteins haptoglobin and hemopexin were among the top proteins originating from plasma and were increased in AD lesional versus healthy skin at baseline (P < .0001). Dupilumab treatment resulted in significantly reduced levels of plasma proteins in AD skin (P < .0001), with most dropping to levels seen in healthy skin or no longer detectable at week 16. CONCLUSIONS: Inhibition of IL-4/IL-13 action by dupilumab significantly reduces the efflux of plasma proteins into AD skin. Several of these proteins, such as fibrinogens and fibronectin, are known to enhance Staphylococcus aureus colonization and are associated with AD skin severity.

Dupilumab significantly improves skin barrier function in patients with moderate-to-severe atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is characterized by abnormal skin lipids that are largely driven by hyperactivated type 2 immune responses. The antibody to the α-subunit of interleukin (IL)-4 receptor, dupilumab, was recently approved to treat AD and demonstrated strong efficacy. However, the role of dupilumab therapy in the regulation of skin barrier structure and function has not been fully explored. METHODS: We have evaluated the content of lipids and transepidermal water loss (TEWL) in lesional and non-lesional skin of adults and adolescents with moderate-to-severe AD over the course of 16-week treatment with dupilumab and compared those values with that of matched healthy volunteers. RESULTS: Dupilumab treatment provided a significant decrease in TEWL in AD lesions, lowering it almost to the levels seen in the skin of healthy subjects. Blocking IL-4/IL-13 signaling with dupilumab normalized lipid composition (decreased levels of ceramides with non-hydroxy fatty acids and C18-sphingosine and increased the level of esterified omega-hydroxy fatty acid-containing ceramides) and increased ceramide chain length in lesional as well as non-lesional stratum corneum of AD patients. Partial changes for these parameters were already observed after 2 weeks, with a full response achieved after 8 weeks of dupilumab treatment. CONCLUSIONS: Inhibition of IL-4/IL-13 signaling by dupilumab allows restoration of skin lipid composition and barrier function in patients with moderate-to-severe AD.

Defective fractalkine-CX3CR1 signaling aggravates neuroinflammation and affects recovery from cuprizone-induced demyelination.

Microglia have been implicated in multiple sclerosis (MS) pathogenesis. The fractalkine receptor CX3CR1 limits the activation of pathogenic microglia and the human polymorphic CX3CR1I249/M280 (hCX3CR1I249/M280 ) variant increases disease progression in models of MS. However, the role of hCX3CR1I249/M280 variant on microglial activation and central nervous system repair mechanisms remains unknown. Therefore, using transgenic mice expressing the hCX3CR1I249/M280 variant, we aimed to determine the contribution of defective CX3CR1 signaling to neuroinflammation and remyelination in the cuprizone model of focal demyelination. Here, we report that mice expressing hCX3CR1I249/M280 exhibit marked demyelination and microgliosis following acute cuprizone treatment. Nanostring gene expression analysis in demyelinated lesions showed that hCX3CR1I249/M280 but not CX3CR1-deficient mice up-regulated the cuprizone-induced gene profile linked to inflammatory, oxidative stress, and phagocytic pathways. Although CX3CR1-deficient (CX3CR1-KO) and fractalkine-deficient (FKN-KO) mice displayed a comparable demyelination and microglial activation phenotype to hCX3CR1I249/M280 mice, only CX3CR1-deficient and CX3CR1-WT mice showed significant myelin recovery 1 week from cuprizone withdrawal. Confocal microscopy showed that hCX3CR1I249/M280 variant inhibits the generation of cells involved in myelin repair. Our results show that defective fractalkine signaling contributes to regional differences in demyelination, and suggest that the CX3CR1 pathway activity may be a key mechanism for limiting toxic gene responses in neuroinflammation. Cover Image for this issue: https://doi.org/10.1111/jnc.15416.

Unique skin abnormality in patients with peanut allergy but no atopic dermatitis.

BACKGROUND: The nonlesional skin of children with atopic dermatitis (AD) with peanut allergy (PA) is associated with increased transepidermal water loss; low urocanic acid (UCA) and pyrrolidone carboxylic acid (PCA), both of which are filaggrin breakdown products; and a reduced ratio of esterified ω-hydroxy fatty acid sphingosine ceramides (EOS-CERs) to nonhydroxy fatty acid sphingosine ceramides (NS-CERs) in the skin. The skin barrier of subjects with PA without AD (AD-PA+) has not been studied. OBJECTIVE: Our aim was to explore whether AD-PA+ is associated with skin barrier abnormalities. METHODS: A total of 33 participants were enrolled, including 13 AD-PA+, 9 AD+PA+, and 11 nonatopic (NA) participants. RESULTS: The PCA content in the stratum corneum of AD-PA+ subjects was significantly reduced versus that in NA subjects (median level, 67 vs 97 µg/mg protein [P = .028]). The ratio between cis- and trans-UCA decreased significantly from being highest in the NA group (1.62) to lowest in AD+PA+ group (0.07 [P < .001 vs in the NA group; P = .006 vs in the AD-PA+ group]), with the AD-PA+ group having an intermediate cis/trans-UCA ratio (1.17 [P = .024 vs in the NA group]). The TEWL in AD-PA+ subjects did not differ from that in the group with NA skin. Interestingly, AD-PA+ subjects had an increased EOS/NS-CER ratio versus that in the group of subjects with NA skin (1.9 vs 1.3 [P = .008]), whereas the AD+PA+ group had a decreased proportion of EOS-CERs (0.8 [P = .001] vs in the AD-PA+ group). CONCLUSION: Our data demonstrate that irrespective of AD, PA is associated with decreased skin cis-UCA and PCA content. An increase in skin EOS-CER/NS-CER ratio separates the AD-PA+ group from the AD+PA+ and NA groups.

Cumulative risk assessment toolbox: methods and approaches for the practitioner.

The historical approach to assessing health risks of environmental chemicals has been to evaluate them one at a time. In fact, we are exposed every day to a wide variety of chemicals and are increasingly aware of potential health implications. Although considerable progress has been made in the science underlying risk assessments for real-world exposures, implementation has lagged because many practitioners are unaware of methods and tools available to support these analyses. To address this issue, the US Environmental Protection Agency developed a toolbox of cumulative risk resources for contaminated sites, as part of a resource document that was published in 2007. This paper highlights information for nearly 80 resources from the toolbox and provides selected updates, with practical notes for cumulative risk applications. Resources are organized according to the main elements of the assessment process: (1) planning, scoping, and problem formulation; (2) environmental fate and transport; (3) exposure analysis extending to human factors; (4) toxicity analysis; and (5) risk and uncertainty characterization, including presentation of results. In addition to providing online access, plans for the toolbox include addressing nonchemical stressors and applications beyond contaminated sites and further strengthening resource accessibility to support evolving analyses for cumulative risk and sustainable communities.

Toxicity assessment of complex mixtures remains a goal.

One of the initial steps in remediating contaminated environments is to assess the human and ecological health risk associated with exposure to contaminants in a specific medium. Presented here are the results of a five-year study investigating the toxicity of simple and complex mixtures. A series of model compounds and simple mixtures including polycyclic aromatic hydrocarbons (PAHs), pentachlorophenol (PCP), and halogenated aliphatic hydrocarbons (HAHs) were analyzed. Mixture toxicity was studied using microbial genotoxicity assays and cytotoxicity assays with renal and neural cells. The majority of binary mixtures described here induced additive responses. A limited number of samples were identified where binary mixtures induced inhibitory effects. For example, benzo(a)pyrene (BAP) alone induced 30% renal cell death, whereas an equimolar dose of chrysene and BAP only produced 1.6% cellular death. In none of the mixtures tested did the mixture toxicity results deviate from the predicted results by an order of magnitude. The results from testing binary mixtures in this study indicate that the results did not deviate significantly from additivity. Complex mixture results were more difficult to interpret. The toxicity of complex mixtures could not be accurately predicted based on chemical analysis. This could be due to chemical interactions or due to the presence of unidentified chemicals, such as alkyl PAHs or high molecular weight PAHs that are not included in the standard risk assessment procedure. Even though the results from these in vitro studies indicate that additive assumptions will generally be appropriate for binary mixtures similar to the ones tested here, the risk associated with complex mixtures remains a challenge to predict. Before the results of toxicity testing can be used to adjust risk assessment calculations, it is important to fully appreciate the chemical composition and to understand the mechanism of observed chemical interactions in animals chronically exposed to low doses of chemical mixtures. This research was supported by ATSDR Grant no. ATU684505 and NIEHS SBRP Grant no. P42 ES04917.