Inflammatory loops in the epithelial-immune microenvironment of the skin and skin appendages in chronic inflammatory diseases

Abstract

The epithelial-immune microenvironment (EIME) of epithelial tissues has five common elements: (1) microbial flora, (2) barrier, (3) epithelial cells, (4) immune cells, and (5) peripheral nerve endings. EIME provides both constant defense and situation-specific protective responses through three-layered mechanisms comprising barriers, innate immunity, and acquired immunity. The skin is one of the largest organs in the host defense system. The interactions between the five EIME elements of the skin protect against external dangers from the environment. This dysregulation can result in the generation of inflammatory loops in chronic inflammatory skin diseases. Here, we propose an understanding of EIME in chronic skin diseases, such as atopic dermatitis, psoriasis, systemic lupus erythematosus, alopecia areata, and acne vulgaris. We discuss the current treatment strategies targeting their inflammatory loops and propose possible therapeutic targets in the future.

Keywords: EIME; alopecia areata; and acne; atopic dermatitis; psoriasis; systemic lupus erythematosus.

Figure 1

The epithelial–immune microenvironment (EIME) of the skin and skin appendages. There are five common elements in the microenvironment of epithelial tissues: microbial flora, barrier, epithelial cells, immune cells, and peripheral nerve endings. The interaction between these five elements provides protection against dangers from the environment.

Figure 2

Inflammatory loops in the epithelial–immune microenvironment (EIME) of chronic inflammatory diseases (A) Loops in atopic dermatitis. Two inflammatory loops drive type 2 EIME in skin lesions in AD. One is the loop between epithelial and immune cells, which constructs T_H2 interplay. The other is a loop involving S. aureus-dominant dysbiosis and abnormal sensory nerve endings that cause pruritus. (B) A loop in psoriasis. A single inflammatory loop between epithelial and immune cells in the interleukin (IL)-23–IL-17 axis drives type 17 EIME in lesional skin in psoriasis. The skin microbiome remains unchanged, suggesting less involvement of microbial flora, whereas C albicans colonization elicits a type 17 response by directly stimulating the sensory nerve endings. (C) Loops in systemic erythematosus (SLE). An inflammatory loop between epithelial cells, microbial flora, and immune cells is drawn in the EIME of lesional skin in SLE. Another loop may be organized without microbial flora. Keratinocyte damage caused by sunlight or microbial flora can trigger these loops. The plasmacytoid dendritic cells (pDCs) promote these loops only during the initiation phase by releasing type I interferons (IFN-I). The constitutive activation of Toll-like receptor (TLR)7/9 drives type-I IFN loops. Neutrophil extracellular traps (NET) activate pDCs at an early stage and promote disease propagation. (D) A loop in alopecia areata (AA). A single inflammatory loop of interferon (IFN)-γ and IL-15 is driven by the EIME of hair follicles (HFs) in the anagen phase. The outer root sheath (ORS) cells of HFs express abnormal or ectopic major histocompatibility complex (MHC) molecules and NKG2D ligands. IFN-γ produced from NKG2D⁺ T cells and NK cells induce hair loss and promote the expression of these molecules, and IL-15, from the HF ORS cells. IL-15 activates IFN-γ-producing cells. (E) Loops in acne vulgaris. The inflammatory loops in acne vulgaris involve sebocytes, infundibular cells, Cutibacterium acnes, and immune cells. An increase in androgen levels triggers these loops. Comedogenesis is a bottleneck in acne pathophysiology. AMPs, antimicrobial peptides; BNP, brain-derived natriuretic peptide; CCL, C-C motif ligand; CGRP, calcitonin gene-related peptide; CXCL, C-X-C motif ligand; DCs, dendritic cells; IFN, interferon; IL, interleukin; ILC, innate lymphoid cell; LCs, Langerhans cells; LTC₄, leukotriene C4; NET, Neutrophil extracellular trap; NK, natural killer; ORS, outer root sheath; PAMPs, pathogen-associated molecular patterns; pDCs, plasmacytoid dendritic cells; T_H2, T helper type 2; TLR, Toll-like receptor.