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Key Points Type 2 inflammation, which encompasses systemic T helper 2 (T H 2)-type responses, is emerging as a unifying feature of both classically defined allergic diseases such as asthma and a range of other inflammatory diseases. Although immunological diseases may appear disparate based on their distinct organ or tissue manifestations, the tendency for diverse allergic diseases to present as co-morbidities or progressively suggests that they may share common underlying drivers. The proximal type 2 cytokines interleukin-4 (IL-4), IL-5 and IL-13, produced by both innate and T H 2 cells, contribute to the hallmarks of type 2-driven diseases, such as elevated immunoglobulin E (IgE) production and systemic and tissue-infiltrated eosinophilia. Early clinical studies in asthma targeting IL-4, IL-5 and IL-13 did not lead to clear efficacy, possibly owing to the molecular properties of the blockers, route of administration, bioavailability and/or incorrect study patient population. However, these studies contributed to a growing understanding of the heterogeneity of asthma that led to the successful targeting of IL-4, IL-5 and/or IL-13 in subsets of patients with high biomarkers of type 2 inflammation. Probing the molecular underpinnings of atopic dermatitis also revealed prominent type 2 inflammation. Although targeting IgE or IL-5 alone did not show clinical effects in atopic dermatitis, dual blockade of IL-4 and IL-13 demonstrated significant efficacy, confirming that type 2 inflammation mediates atopic dermatitis. The success of systemic IL-4 and IL-13 blockade across three allergic diseases with disparate specific tissue manifestations — asthma, atopic dermatitis and chronic sinusitis with nasal polyps — suggests that the IL-4–IL-13 pathway is a key central driver pathway in immunological diseases. Rather than defining atopic diseases by their apparent tissue manifestations, the identification of driver pathways in these three diseases suggests that immunological diseases can be defined and grouped based on their driver immunological pathways to enable tailored therapy. Inflammatory conditions such as asthma, atopic dermatitis and chronic sinusitis with nasal polyps are caused by type 2 inflammation. In this Review, Gandhi et al . explore the idea that these conditions can be treated by targeting the common proximal drivers of type 2 inflammation, which include interleukin-4 (IL-4), IL-5 and IL-13, and discuss the supporting clinical evidence as well as candidate drugs in development. Systemic type 2 inflammation encompassing T helper 2 (T H 2)-type responses is emerging as a unifying feature of both classically defined allergic diseases, such as asthma, and a range of other inflammatory diseases. Rather than reducing inflammation with broad-acting immunosuppressants or narrowly targeting downstream products of the T H 2 pathway, such as immunoglobulin E (IgE), efforts to target the key proximal type 2 cytokines — interleukin-4 (IL-4), IL-5 and IL-13 — represent a promising strategy to achieve therapeutic benefit across multiple diseases. After several initial disappointing clinical results with therapies targeting IL-4, IL-5 or IL-13 in asthma, applying a personalized approach achieved therapeutic benefit in an asthma subtype exhibiting an 'allergic' phenotype. More recently, efficacy was extended into a broad population of people with asthma. This argues that the Type 2 inflammation is broadly relevant across the severe asthma population if the key upstream drivers are properly blocked. Moreover, the simultaneous inhibition of IL-4 and IL-13 has shown significant clinical activity in diseases that are often co-morbid with asthma — atopic dermatitis and chronic sinusitis with nasal polyps — supporting the hypothesis that targeting a central 'driver pathway' could benefit multiple allergic diseases.

Allergic skin diseases, such as atopic dermatitis, are clinically characterized by severe itching and type 2 immunity-associated hypersensitivity to widely distributed allergens, including those derived from house dust mites (HDMs). Here we found that HDMs with cysteine protease activity directly activated peptidergic nociceptors, which are neuropeptide-producing nociceptive sensory neurons that express the ion channel TRPV1 and Tac1, the gene encoding the precursor for the neuropeptide substance P. Intravital imaging and genetic approaches indicated that HDM-activated nociceptors drive the development of allergic skin inflammation by inducing the degranulation of mast cells contiguous to such nociceptors, through the release of substance P and the activation of the cationic molecule receptor MRGPRB2 on mast cells. These data indicate that, after exposure to HDM allergens, activation of TRPV1+Tac1+ nociceptor–MRGPRB2+ mast cell sensory clusters represents a key early event in the development of allergic skin reactions.

Atopic dermatitis (AD) is a skin disease exhibiting clinical and molecular heterogeneity, thereby jeopardizing the development of personalized treatments. Here we pursue a cross-sectional and longitudinal cohort analysis of 951 whole-skin samples, employing an unsupervised decomposition analysis to link gene expression profiles to disease severity, six distinct skin phenotypes, and blood cytokines representative of given endotypes. Specifically, type 2 and type 17 responses are associated with major skin phenotypes such as erythema and induration, while type 1 response is upregulated in lichen amyloidosis of AD patients. Longitudinal analysis of patients treated with dupilumab finds sustained gene signatures related to type 17 response in lesional skin and upregulated transcription factors in non-lesional skin of patients with poor treatment outcomes. Lastly, several extracellular matrix organization-associated genes are correlated with clinical severity and treatment response to dupilumab. Our findings thus provide potential skin and blood biomarkers for assessing endotypes and therapeutic responses in AD to pave the way for personalized medicine. Atopic dermatitis (AD) with complex manifestations and genetic associations. Here the author profile the transcriptome of 951 skin samples from patients with AD to link skin phenotypes, clinical severity, and efficacy of dupilumab treatment to specific types of immune responses and gene features to serve clues for personalized medicine.

Atopic dermatitis (AD) is a skin disease that is heterogeneous both in terms of clinical manifestations and molecular profiles. It is increasingly recognized that AD is a systemic rather than a local disease and should be assessed in the context of whole-body pathophysiology. Here we show, via integrated RNA-sequencing of skin tissue and peripheral blood mononuclear cell (PBMC) samples along with clinical data from 115 AD patients and 14 matched healthy controls, that specific clinical presentations associate with matching differential molecular signatures. We establish a regression model based on transcriptome modules identified in weighted gene co-expression network analysis to extract molecular features associated with detailed clinical phenotypes of AD. The two main, qualitatively differential skin manifestations of AD, erythema and papulation are distinguished by differential immunological signatures. We further apply the regression model to a longitudinal dataset of 30 AD patients for personalized monitoring, highlighting patient heterogeneity in disease trajectories. The longitudinal features of blood tests and PBMC transcriptome modules identify three patient clusters which are aligned with clinical severity and reflect treatment history. Our approach thus serves as a framework for effective clinical investigation to gain a holistic view on the pathophysiology of complex human diseases. Atopic dermatitis is an inflammatory skin disease featuring systemic involvement. Here authors show that the two major clinical manifestations of the disease, erythema and papulation, are distinguished by differential interplay between local skin and systemic immunity, uncovered by integrated transcriptomics.

Interleukin-2-inducible T cell kinase is expressed by T cells and amplifies T cell receptor-dependent signals. Interleukin-2-inducible T cell kinase deletion or inhibition reduces production of interleukin-4 and interleukin-13, key drivers of atopic dermatitis. Nerve growth factor signals via the receptor tropomyosin-related kinase A and may promote pruritus in atopic dermatitis lesions. Here we describe PF-07245303, a compound which potently inhibits interleukin-2-inducible T cell kinase and tropomyosin-related kinase family kinases capable of inhibiting T cell receptor-mediated cytokine production from CD4 and CD8 T cells and suppressing nerve growth factor-induced human basophil activation. In human skin explants, PF-07245303 demonstrates inhibition of tropomyosin-related kinase A phosphorylation, suppresses cytokine expression from T cell receptor-activated resident T cells and reverses the expression of atopic dermatitis associated genes. Topical application of PF-07245303 reduces proinflammatory and epidermal changes in a dermatitis model using female mice. By inhibiting both pathogenic inflammatory mechanisms, PF-07245303 may have therapeutic value for patients with atopic dermatitis. Atopic dermatitis is an immune disease driven by cytokines including IL-4/IL-13. This study shows that a topical ITK/TRK inhibitor blocks an array of T cell cytokines, inhibits NGF-induced basophil activation, and reduces inflammation in human skin explants and dermatitis models, indicating therapeutic potential.

The epithelial and epidermal innate cytokines IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) have pivotal roles in the initiation of allergic inflammation in asthma and atopic dermatitis (AD). However, the mechanism by which the expression of these innate cytokines is regulated remains unclear. Intelectin (ITLN) is expressed in airway epithelial cells and promotes allergic airway inflammation. We hypothesized that ITLN is required for allergen-induced IL-25, IL-33, and TSLP expression. In two asthma models, Itln knockdown reduced allergen-induced increases in Il-25, Il-33, and Tslp and development of type 2 response, eosinophilic inflammation, mucus overproduction, and airway hyperresponsiveness. Itln knockdown also inhibited house dust mite (HDM)-induced early upregulation of Il-25, Il-33, and Tslp in a model solely inducing airway sensitization. Using human airway epithelial cells, we demonstrated that HDM-induced increases in ITLN led to phosphorylation of epidermal growth factor receptor and extracellular-signal regulated kinase, which were required for induction of IL-25, IL-33, and TSLP expression. In two AD models, Itln knockdown suppressed expression of Il-33, Tslp, and Th2 cytokines and eosinophilic inflammation. In humans, ITLN1 expression was significantly increased in asthmatic airways and in lesional skin of AD. We conclude that ITLN contributes to allergen-induced Il-25, Il-33, and Tslp expression in asthma and AD.

Regulation of cutaneous immunity is severely compromised in inflammatory skin disease. To investigate the molecular crosstalk underpinning tolerance versus inflammation in atopic dermatitis, we utilise a human in vivo allergen challenge study, exposing atopic dermatitis patients to house dust mite. Here we analyse transcriptional programmes at the population and single cell levels in parallel with immunophenotyping of cutaneous immunocytes revealed a distinct dichotomy in atopic dermatitis patient responsiveness to house dust mite challenge. Our study shows that reactivity to house dust mite was associated with high basal levels of TNF-expressing cutaneous Th17 T cells, and documents the presence of hub structures where Langerhans cells and T cells co-localised. Mechanistically, we identify expression of metallothioneins and transcriptional programmes encoding antioxidant defences across all skin cell types, that appear to protect against allergen-induced inflammation. Furthermore, single nucleotide polymorphisms in the MTIX gene are associated with patients who did not react to house dust mite, opening up possibilities for therapeutic interventions modulating metallothionein expression in atopic dermatitis. Inflammatory skin diseases are frequently associated with dysregulation of cutaneous immunity. Here the authors perform human challenge with house dust mite allergen in patients with atopic dermatitis and explore the molecular network determining tolerance versus inflammation and identify a role for metallothioneins in the modulation of allergen induced inflammation.

The relationship between atopic dermatitis and air pollution has been long debated but has now been connected via the aryl hydrocarbon receptor and its control of skin innervation and the consequent triggering of an itch-scratch response.

Filaggrin ( FLG ) mutation is a well-confirmed genetic aberration in atopic dermatitis (AD). Genome-wide association studies on AD have revealed other susceptibility genes, for example, Ovo-like 1 (OVOL1). Nonetheless, the relation between FLG and OVOL1 is unclear. Because aryl hydrocarbon receptor (AHR; a ligand-activated transcription factor), plays a role in FLG expression in keratinocytes, we hypothesized that AHR regulates FLG expression via OVOL1. To demonstrate this mechanism, we analyzed FLG expression in OVOL1-overexpressing or OVOL1-knockdown normal human epidermal keratinocytes (NHEKs). Furthermore, we tested whether AHR activation by 6-formylindolo(3,2-b)carbazole (FICZ), an endogenous AHR ligand, or Glyteer, clinically used soybean tar, upregulates FLG and OVOL1 expression in NHEKs. We found that (1) OVOL1 regulates FLG expression; (2) AHR activation upregulates OVOL1; and (3) AHR activation upregulates FLG via OVOL1. Moreover, nuclear translocation of OVOL1 was less pronounced in AD skin compared with normal skin. IL-4-treated NHEKs, an in vitro AD skin model, also showed inhibition of the OVOL1 nuclear translocation, which was restored by FICZ and Glyteer. Thus, targeting the AHR–OVOL1–FLG axis may provide new therapeutics for AD.

The main factors involved in the pathogenesis of atopic dermatitis (AD) are skin barrier abnormality, allergy/immunology, and pruritus. Considering how oxidative stress influences these factors, antioxidant agents may be effective candidates in the treatment of AD. To evaluate the effect of Caffeoyl–Pro–His amide (CA-PH), an antioxidant agent, on 2,4-dinitrochlorobenzene (DNCB)-induced AD-like phenotypes in BALB/c mice. Topical sensitization and challenge by DNCB were performed on the dorsal skin of BALB/c mice to induce AD-like cutaneous lesions, phenotypes, and immunologic response. CA-PH was applied topically for 2 weeks to assess its effects on DNCB-induced AD-like phenotypes. As a result, CA-PH relieved DNCB-induced AD-like phenotypes quantified by dermatitis severity score, scratching duration, and trans-epidermal water loss. Histopathological analysis showed that CA-PH decreased epidermal thickening, the number of mast cells, and eosinophil infiltration in dermis. Immunohistochemical staining revealed that CA-PH recovered skin barrier-related proteins: filaggrin, involucrin, and loricrin. As for the immunologic aspects, CA-PH treatment lowered mRNA or protein levels of interleukin (IL)-4, IL-6, IL-17a, IL-1b, IL-31, and IL-33 levels and thymic stromal lymphopoietin (TSLP) levels in cutaneous tissue, reducing the DNCB-induced serum IgE level elevation. In conclusion, topical CA-PH may be a therapeutic option for the treatment of AD.