Atopic dermatitis: pathogenesis and therapeutic intervention

Abstract

The skin serves as the first protective barrier for nonspecific immunity and encompasses a vast network of skin-associated immune cells. Atopic dermatitis (AD) is a prevalent inflammatory skin disease that affects individuals of all ages and races, with a complex pathogenesis intricately linked to genetic, environmental factors, skin barrier dysfunction as well as immune dysfunction. Individuals diagnosed with AD frequently exhibit genetic predispositions, characterized by mutations that impact the structural integrity of the skin barrier. This barrier dysfunction leads to the release of alarmins, activating the type 2 immune pathway and recruiting various immune cells to the skin, where they coordinate cutaneous immune responses. In this review, we summarize experimental models of AD and provide an overview of its pathogenesis and the therapeutic interventions. We focus on elucidating the intricate interplay between the immune system of the skin and the complex regulatory mechanisms, as well as commonly used treatments for AD, aiming to systematically understand the cellular and molecular crosstalk in AD-affected skin. Our overarching objective is to provide novel insights and inform potential clinical interventions to reduce the incidence and impact of AD.

Keywords: atopic dermatitis; immune cells; pathophysiology; therapeutic intervention.

FIGURE 1

Skin barrier dysfunction and the role of keratinocytes in AD. The skin is composed of the epidermis, dermis, and subcutaneous tissue, with the epidermis itself subdivided into four distinct layers. Keratinocytes, the predominant cell type within the epidermis, play a crucial role in maintaining skin barrier integrity. In atopic dermatitis (AD), the absence of key genes such as Filaggin (FLG) in keratinocytes diminishes the expression of tight junction proteins. This resulting in compromised barrier function and disruption alters the localization of tight junctions within the granular layer. Concurrently, keratinocytes secrete inflammatory cytokines and chemokines, which exacerbate the inflammatory response characteristic of AD. The associated pruritus in patients further damages the skin barrier, contributing to increased transepidermal water loss. This figure was drawn by BioRender.com.

FIGURE 2

Immunological imbalances and cellular interactions in AD. Immune dysregulation, particularly T cell‐mediated responses, play a pivotal role in the pathogenesis of AD. A compromised skin barrier increases susceptibility to environmental allergens, triggering the activation of antigen‐presenting cells that stimulate T cells and initiate a cascade of inflammatory responses. Additionally, keratinocytes contribute to this process by secreting inflammatory mediators that promote immune cell infiltration into AD‐lesions, further exacerbating inflammation. The interactions among keratinocytes, fibroblasts, innate immune cells such as type 2 innate lymphoid cells, mast cells, basophils, eosinophils, monocytes, and macrophages, as well as adaptive immune cells (T cells and B cells) play a pivotal role in the pathogenesis and progression of AD. This figure was drawn by BioRender.com.

FIGURE 3

Participation of skin dendritic cells in pathogenesis of AD. In response to external stimuli, both LCs and dDCs migrate to the draining LN, but CD207⁺dDC migrate faster than LCs. LCs and dDCs are crucial for delivering antigens to CD4⁺T cells and promoting Th2 differentiation which in turn regulates the development of AD. TSLP, thymic stromal lymphopoietin; CCL17, chemokine ligand 17; CCL19, chemokine ligand 19. This figure was drawn by Figdraw.

FIGURE 4

Th cells in pathogenesis of AD. Skin‐tropic effector T cell clones originate from naïve T cell precursors. Following skin barrier damage, various microbial invasions and antigen‐presenting cells activate T cells, triggering a cascade of T cell responses. These activated cells migrate to sites of inflammation, releasing inflammatory cytokines that exacerbate the progression of AD.

FIGURE 5

Role of cytokines in AD. Significant quantities of cytokines such as IL‐25, IL‐33, and TSLP to coordinate the infiltration of immune cells into the AD‐lesional skin. The upregulation of these cytokines activates ILC2s, leading to the production of type 2 inflammation‐associated cytokines, including IL‐4. Consequently, this cytokine release influences the infiltration of other cells, such as eosinophils and basophils. This figure was drawn by Figdraw.

FIGURE 6

A summary of in vivo models for AD. Numerous mouse models have been created for the study of AD. In addition to generating humanized models of AD through the transplantation of human immune cells or skin tissue, different categories of AD models exist. These include models induced by topically applying sensitizers on the skin, transgenic mice that exhibit either excessive or deficient levels of specific molecules relevant to AD, and mice that spontaneously develop cutaneous lesions resembling those seen in individuals with AD. This figure was drawn by BioRender.com.

FIGURE 7

A summary of in vitro models for AD. To gain a comprehensive understanding of the inflammatory process underlying AD and conduct thorough investigations, various in vitro models have been developed. These include 2D monolayer and coculture systems, advanced 3D skin models including reconstructed human epidermis (RHE) and full‐thickness human skin equivalents (HSE), as well as innovative skin‐on‐a‐chip systems that accurately represent skin. This figure was drawn by BioRender.com.