bites promote allergic skin inflammation and intestinal tuft and mast cell expansion in mice.

Background: Tick bites often promote local allergic reactions in the skin and predispose to red meat allergy. The mechanisms involved in these processes are not fully understood. Here we investigated the local changes to the skin and intestine induced by tick bites.

IL-4 acts on skin-derived dendritic cells to promote the T2 response to cutaneous sensitization and the development of allergic skin inflammation.

Background: Atopic dermatitis is characterized by scratching and a T2-dominated local and systemic response to cutaneously encountered antigens. Dendritic cells (DCs) capture antigens in the skin and rapidly migrate to draining lymph nodes (dLNs) where they drive the differentiation of antigen-specific naive T cells.

Objective: We sought to determine whether non-T-cell-derived IL-4 acts on skin-derived DCs to promote the T2 response to cutaneously encountered antigen and allergic skin inflammation.

Basophils are important for development of allergic skin inflammation.

Background: Atopic dermatitis skin lesions exhibit increased infiltration by basophils. Basophils produce IL-4, which plays an important role in the pathogenesis of atopic dermatitis.

Objective: We sought to determine the role of basophils in a mouse model of antigen-driven allergic skin inflammation.

Basophils Play a Protective Role in the Recovery of Skin Barrier Function from Mechanical Injury in Mice.

Physical trauma disrupts skin barrier function. How the skin barrier recovers is not fully understood. We evaluated in mice the mechanism of skin barrier recovery after mechanical injury inflicted by tape stripping.

Regulatory T-cell dysfunction and cutaneous exposure to Staphylococcus aureus underlie eczema in DOCK8 deficiency.

Background: Dedicator of cytokinesis 8 (DOCK8)-deficient patients have severe eczema, elevated IgE, and eosinophilia, features of atopic dermatitis (AD).

Objective: We sought to understand the mechanisms of eczema in DOCK8 deficiency.

Methods: Skin biopsy samples were characterized by histology, immunofluorescence microscopy, and gene expression.

S. aureus drives itch and scratch-induced skin damage through a V8 protease-PAR1 axis.

Itch is an unpleasant sensation that evokes a desire to scratch. The skin barrier is constantly exposed to microbes and their products. However, the role of microbes in itch generation is unknown.

Multi-modal skin atlas identifies a multicellular immune-stromal community associated with altered cornification and specific T cell expansion in atopic dermatitis.

In healthy skin, a cutaneous immune system maintains the balance between tolerance towards innocuous environmental antigens and immune responses against pathological agents. In atopic dermatitis (AD), barrier and immune dysfunction result in chronic tissue inflammation. Our understanding of the skin tissue ecosystem in AD remains incomplete with regard to the hallmarks of pathological barrier formation, and cellular state and clonal composition of disease-promoting cells.

Tick salivary glycans - a sugar-coated tick bite.

Ticks are hematophagous arthropods that transmit disease-causing pathogens worldwide. Tick saliva deposited into the tick-bite site is composed of an array of immunomodulatory proteins that ensure successful feeding and pathogen transmission. These salivary proteins are often glycosylated, and glycosylation is potentially critical for the function of these proteins.

Ant Venom-Based Ceramide Therapy Is Effective Against Atopic Dermatitis In Vivo.

Background: Atopic dermatitis (AD) is a common skin condition with relatively few therapeutic alternatives. These include corticosteroids, which address inflammation but not superinfection, and Januse kinase (JAK) inhibitors, which have a US Food and Drug Administration (FDA) black box for potential carcinogenicity.

Methods: We demonstrate that S14, a synthetic derivative of ant venom-derived solenopsin, has potent anti inflammatory effects on the OVA murine model of atopic dermatitis.

IL-4 receptor alpha blockade dampens allergic inflammation and upregulates IL-17A expression to promote Saureus clearance in antigen sensitized mouse skin.

Background: Skin colonization with Staphylococcus aureus aggravates atopic dermatitis and exaggerates allergic skin inflammation in mice. IL-4 receptor α (IL-4Rα) blockade is beneficial in atopic dermatitis and reduces Saureus skin colonization through unknown mechanisms. The cytokine IL-17A restrains Saureus growth.

The IL-4Rα Q576R polymorphism is associated with increased severity of atopic dermatitis and exaggerates allergic skin inflammation in mice.

Background: Atopic dermatitis (AD) is characterized by T2-dominated skin inflammation and systemic response to cutaneously encountered antigens. The T2 cytokines IL-4 and IL-13 play a critical role in the pathogenesis of AD. The Q576->R576 polymorphism in the IL-4 receptor alpha (IL-4Rα) chain common to IL-4 and IL-13 receptors alters IL-4 signaling and is associated with asthma severity.

Single-cell transcriptome profile of mouse skin undergoing antigen-driven allergic inflammation recapitulates findings in atopic dermatitis skin lesions.

Background: Allergic skin inflammation elicited in mice by epicutaneous (EC) sensitization with antigen shares characteristics with human atopic dermatitis (AD).

Objective: We characterized gene expression by single cells in mouse skin undergoing antigen-driven allergic inflammation and compared the results with findings in AD skin lesions.

Methods: Mice were EC sensitized by application of ovalbumin (OVA) or saline to tape-stripped skin.

Cutaneous Type 2 Innate Lymphoid Cells Come in Distinct Flavors.

In a new article published in , Nakatani-Kusakabe et al. (2021) show that type 2 innate lymphoid cells (ILC2s) in the skin of mice with IL-33 overexpression in keratinocytes are heterogeneous and consist of two distinct populations: skin-resident ILC2s and circulating ILC2s. They show that the circulating subset of skin ILC2s migrates to draining lymph nodes during hapten-induced cutaneous inflammation to potentially enhance the adaptive immune response.

Basophil-derived IL-4 promotes cutaneous Staphylococcus aureus infection.

Superficial cutaneous Staphylococcus aureus (S. aureus) infection in humans can lead to soft tissue infection, an important cause of morbidity and mortality. IL-17A production by skin TCRγδ+ cells in response to IL-1 and IL-23 produced by epithelial and immune cells is important for restraining S.

Author Correction: A regulatory T cell Notch4-GDF15 axis licenses tissue inflammation in asthma.

A Correction to this paper has been published: https://doi.org/10.1038/s41590-021-00929-x.

Mast cell-derived IL-13 downregulates IL-12 production by skin dendritic cells to inhibit the T1 cell response to cutaneous antigen exposure.

Background: Atopic dermatitis (AD) is characterized by a skin barrier defect aggravated by mechanical injury inflicted by scratching, a T2 cell-dominated immune response, and susceptibility to viral skin infections that are normally restrained by a T1 cell response. The signals leading to a T2 cell-dominated immune response in AD are not completely understood.

Objective: Our aim was to determine the role of IL-13 in initiation of the T cell response to cutaneously encountered antigens.

DOCK8 Expression in Regulatory T Cells Maintains their Stability and Limits Contact Hypersensitivity.

Chronic dermatitis is a hallmark of Dedicator of cytokinesis 8 (DOCK8) deficiency. The migration of DOCK8-deficient T cells to the skin and their survival there have been reported to be defective. Surprisingly, we found that Dock8 mice demonstrated an exaggerated contact hypersensitivity (CHS) response to oxazolone with increased ear swelling, T-cell infiltration, and expression of Ifng.

A regulatory T cell Notch4-GDF15 axis licenses tissue inflammation in asthma.

Elucidating the mechanisms that sustain asthmatic inflammation is critical for precision therapies. We found that interleukin-6- and STAT3 transcription factor-dependent upregulation of Notch4 receptor on lung tissue regulatory T (T) cells is necessary for allergens and particulate matter pollutants to promote airway inflammation. Notch4 subverted T cells into the type 2 and type 17 helper (T2 and T17) effector T cells by Wnt and Hippo pathway-dependent mechanisms.

APRIL expression is upregulated in atopic dermatitis skin lesions and at sites of antigen driven allergic skin inflammation in mice.

Atopic dermatitis (AD) is the most common inflammatory skin disease. It is characterized by a defective skin barrier and a Th2 dominated skin inflammation. The TNF family member a proliferation-inducing ligand (APRIL) and its receptors transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B cell maturation antigen (BCMA) are expressed by immune cells and epithelial cells including keratinocytes.

Allergic skin inflammation and S. aureus skin colonization are mutually reinforcing.

Atopic dermatitis (AD) lesional skin is often colonized with S. aureus, and the load of S. aureus correlates with disease severity.

ILC2 activation by keratinocyte-derived IL-25 drives IL-13 production at sites of allergic skin inflammation.

Background: Atopic dermatitis skin lesions demonstrate increased expression of IL-25 by keratinocytes and increased numbers of type 2 innate lymphoid cells (ILC2s) that express high levels of IL-25 receptor (IL-25R). IL-13 is expressed in atopic dermatitis skin lesions and plays an important role in pathogenesis of the disease.

Objective: Our aim was to determine the role of IL-25 and ILC2s in a mouse model of antigen-driven allergic skin inflammation.

Mechanical Skin Injury Promotes Food Anaphylaxis by Driving Intestinal Mast Cell Expansion.

Mast cell (MC) mediator release after crosslinking of surface-bound IgE antibody by ingested antigen underlies food allergy. However, IgE antibodies are not uniformly associated with food allergy, and intestinal MC load is an important determinant. Atopic dermatitis (AD), characterized by pruritis and cutaneous sensitization to allergens, including foods, is strongly associated with food allergy.

IL-22 promotes allergic airway inflammation in epicutaneously sensitized mice.

Background: Serum IL-22 levels are increased in patients with atopic dermatitis, which commonly precedes asthma in the atopic march. Epicutaneous sensitization in mice results in T2-dominated skin inflammation that mimics atopic dermatitis and sensitizes the airways for antigen challenge-induced allergic inflammation characterized by the presence of both eosinophils and neutrophils. Epicutaneous sensitization results in increased serum levels of IL-22.