IL-4 acts on skin-derived dendritic cells to promote the T_H2 response to cutaneous sensitization and the development of allergic skin inflammation - 10/08/24

Doi : 10.1016/j.jaci.2024.06.021

Juan Manuel Leyva-Castillo, PhD ^a,^⁎^{^{∗
These authors contributed equally to this work.}} , Mrinmoy Das, PhD ^a,^{^{∗
These authors contributed equally to this work.}}, Maria Strakosha, BA ^a, Alex McGurk, BA ^a, Emilie Artru, BSc ^a, Christy Kam, PhD ^a, Mohammed Alasharee, BSc ^a, Duane R. Wesemann, MD, PhD ^b,^c,^d, Michio Tomura, PhD ^e, Hajime Karasuyama, MD, PhD ^f, Frank Brombacher, PhD ^g, Raif S. Geha, MD ^a,^⁎^{^{∗
These authors contributed equally to this work.}}
^a Division of Immunology, Department of Pediatrics, Boston Children’s Hospital, Boston, Mass
^b Division of Allergy and Clinical Immunology, Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass
^c Broad Institute, Cambridge, Mass
^d Ragon Institute, Cambridge, Mass
^e Laboratory of Immunology, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan
^f Inflammation, Infection and Immunity Laboratory, Advanced Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
^g International Center for Genetic Engineering and Biotechnology & University of Cape Town & South Africa Medical Research Council, Cape Town, South Africa

^∗Corresponding author: Juan Manuel Leyva-Castillo, PhD, or Raif S. Geha, MD, Division of Immunology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, One Blackfan Circle, Boston, MA 02115.Division of ImmunologyDepartment of PediatricsBoston Children’s HospitalHarvard Medical SchoolOne Blackfan CircleBostonMA02115

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Abstract

Background

Atopic dermatitis is characterized by scratching and a T_H2-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 T_H2 response to cutaneously encountered antigen and allergic skin inflammation.

Methods

DCs from dLNs of ovalbumin (OVA)-exposed skin were analyzed by flow cytometry and for their ability to polarize OVA-specific naive CD4⁺ T cells. Skin inflammation following epicutaneous sensitization of tape-stripped skin was assessed by flow cytometry of skin cells and real-time quantitative PCR of cytokines. Cytokine secretion and antibody levels were evaluated by ELISA.

Results

Scratching upregulated IL4 expression in human skin. Similarly, tape stripping caused rapid basophil-dependent upregulation of cutaneous Il4 expression in mouse skin. In vitro treatment of DCs from skin dLNs with IL-4 promoted their capacity to drive T_H2 differentiation. DCs from dLNs of OVA-sensitized skin of Il4^−/− mice and CD11c-CreIl4r^flox/− mice, which lack IL-4Rα expression in DCs (DC^Δ/Δll4ra mice), were impaired in their capacity to drive T_H2 polarization compared with DCs from controls. Importantly, OVA-sensitized DC^Δ/Δll4ra mice demonstrated impaired allergic skin inflammation and OVA-specific systemic T_H2 response evidenced by reduced T_H2 cytokine secretion by OVA-stimulated splenocytes and lower levels of OVA-specific IgE and IgG1 antibodies, compared with controls.

Conclusions

Mechanical skin injury causes basophil-dependent upregulation of cutaneous IL-4. IL-4 acts on skin DCs that capture antigen and migrate to dLNs to promote their capacity for T_H2 polarization and drive allergic skin inflammation.

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Key words : Atopic dermatitis, dendritic cells, IL-4, T_H2 polarization, cutaneous sensitization, allergic skin inflammation

Abbreviations used : AD, BMDC, DC, dLN, DT, EC, ILC, MC, OVA, rIL-4, TSLP, WT

Plan

Methods

Mice

Tape stripping of mouse skin

Scratching of human skin

Basophil depletion

RNA extraction and real-time PCR

In vivo antigen priming and analysis of mouse skin DCs

In vitro T_H2 polarization by IL-4–treated DCs

Photoconversion of skin of Kaede mice

EC sensitization

Histology and measurement of epidermal thickness

Skin cell preparation and flow cytometry

Cell culture and in vitro cytokine expression

Statistical analysis

Results

Il4 is expressed in intact skin and its expression increases following mechanical injury

Basophils are recruited to the skin and are essential for the upregulation of cutaneous Il4 expression following mechanical skin injury

TSLP and IL-33 are required for basophil recruitment, but only TSLP is required for cutaneous Il4 mRNA upregulation following mechanical skin injury

IL-4 primes skin-derived DCs to promote T_H2 polarization following cutaneous exposure to antigen

IL-4Rα deficiency impairs the capacity of skin-derived DCs for T_H2 polarization

IL-4Rα deficiency in DCs attenuates allergic skin inflammation elicited by EC sensitization with OVA antigen

Discussion

Maria Strakosha is currently at Korro Bio, Inc, Cambridge, Mass; Alex McGurk at Cornell University, Ithaca, NY; and Emilie Artru at Institut de Recherche Saint-Louis, Paris, France.