Type 2 Inflammation and Its Role in Dermatologic Diseases

Abstract

Atopic dermatitis, prurigo nodularis, and chronic spontaneous urticaria are immune-mediated, inflammatory skin conditions characterized by intense itch and disease-specific skin lesions. Despite their different clinical presentations, the three diseases are unified by an aberrant type 2 immune response involving type 2 cytokines, immune cells, and sensory nerves that may underlie their shared clinical manifestations of inflammation and pruritus. The chronic nature of these conditions is associated with significant impairment in patients' quality of life and psychological disorders, such as anxiety and depression. This article reviews type 2 inflammation and its role in atopic dermatitis, prurigo nodularis, and chronic spontaneous urticaria, focusing on the pathophysiologic drivers of type 2 inflammation in each dermatologic condition. Understanding the shared immune mechanisms that underlie these seemingly distinct skin diseases and other concomitant inflammatory conditions is critical for applying therapeutic interventions targeting the type 2 immune pathway.

Keywords: atopic dermatitis; chronic spontaneous urticaria; cytokine; prurigo nodularis; type 2 inflammation.

FIGURE 1

Overview of types 1, 2, and 3 immune responses. IFN, interferon; IL, interleukin; ILC, innate lymphoid cell; NK, natural killer; Tc, T cytotoxic cell; Th, T helper cell; TNF, tumor necrosis factor.

FIGURE 2

Overview of type 2 inflammation in AD. Skin barrier disruption triggers the release of alarmins (IL‐25, IL‐33, TLSP), which stimulate a type 2 immune response. Type 2 cytokines (IL‐4 and IL‐13) activate immune cells and sensitize neurons to pruritogens, leading to an itch‐scratch cycle. A neuro‐immune feedback loop results in the amplification of type 2 inflammation and further skin barrier disruption through scratching. IL, interleukin; ILC, innate lymphoid cell; Th, T helper cell; TSLP, thymic stromal lymphopoietin. Source: Siegfried et al. [41].

FIGURE 3

Overview of type 2 inflammation in PN. Neurogenic inflammation triggers the release of neuropeptides, which activate immune cells. This leads to the release of type 2 cytokines, resulting in itch and chronic inflammation. Persistent scratching may lead to the formation of nodules. IL‐4 and IL‐13 stimulate fibroblasts, promoting dermal fibrosis. IL, interleukin; ILC, innate lymphoid cell; Th, T helper cell. Source: Kwon et al. [73].

FIGURE 4

Overview of type 2 inflammation in CSU. Mast cell degranulation is induced by IgE antibodies binding to high‐affinity IgE receptors on the mast cell surface and/or by IgG antibodies targeting IgE and high‐affinity IgE receptors. Mast cell activation leads to the release of histamines, followed by leukotrienes, prostaglandins, and cytokines. The release of inflammatory mediators results in the recruitment of immune cells, vasodilation, and activation of skin nerves. A perivascular infiltrate of inflammatory cells is also thought to drive clinical manifestations of CSU. BTK, Bruton's tyrosine kinase pathway; H, histamine; Ig, immunoglobulin; IL, interleukin; ILC, innate lymphoid cell; MRGPRX2, mas‐related G‐protein coupled receptor member; X2, PAR protease‐activated receptor; R, receptor; SYK, spleen tyrosine kinase pathway; Th, T helper cell, TSLP, thymic stromal lymphopoietin. Source: Marzano et al. [95].