Neutrophils in Atopic Dermatitis

Abstract

Neutrophils have a critical role in inflammation. Recent studies have identified their distinctive presence in certain types of atopic dermatitis (AD), yet their exact function remains unclear. This review aims to compile studies elucidating the role of neutrophils in AD pathophysiology. Proteins released by neutrophils, including myeloperoxidase, elastase, and lipocalin, contribute to pruritus progression in AD. Neutrophilic oxidative stress and the formation of neutrophil extracellular traps may further worsen AD. Elevated neutrophil elastase and high-mobility group box 1 protein expression in AD patients' skin exacerbates epidermal barrier defects. Neutrophil-mast cell interactions in allergic inflammation steer the immunological response toward Th2 imbalance and activate the Th17 pathway, particularly in response to allergens or infections linked to AD. Notably, drugs alleviating pruritic symptoms in AD inhibit neutrophilic inflammation. In conclusion, these findings underscore that neutrophils may be therapeutic targets for AD symptoms, emphasizing their inclusion in AD treatment strategies.

Keywords: Neutrophil; Atopic dermatitis; Inflammation; Pruritus; Skin lesions.

Fig. 1

Neutrophils in atopic dermatitis. AD originates from a complex interplay of both internal and external factors, which include allergic reactions, exposure to antigens, physical trauma, infections, and emotional stress. Immune responses are orchestrated by neutrophils, B cells, mast cells, and T cells, which release various chemokines and cytokines, such as IgE, IL-4 and IL-13, CXCL1, CXCL2, CXCL8, TNF-α, or LTB4. These substances mediate the recruitment and activation of neutrophils, a crucial component of inflammation. Neutrophils utilize multiple mechanisms during inflammation, including respiratory burst, degranulation, and the formation of neutrophil extracellular traps (NETs). In patients with AD, enhanced neutrophil activity is observed during flare-ups and colonization by S. aureus, leading to excessive oxidative stress. The respiratory burst involves the activation of NADPH oxidase (NOX2) and myeloperoxidase (MPO), which generate superoxide anion (O₂^•−) and reactive oxygen species (ROS). Upon activation, neutrophils release granular compounds, including neutrophil elastase (NE) and MPO, through a process known as degranulation. NETs, composed of extruded chromatin and antimicrobial compounds such as MPO and NE, contribute to inflammatory processes and are implicated in the pathogenesis of AD. Continued production of IL-17 by NETs and the subsequent stimulation of Th17 cells to release more IL-17 is a crucial process. This plays a pivotal role in initiating and enhancing neutrophil infiltration, which is a fundamental aspect of the immune response in AD. During the transition from acute to chronic lesions, there is an elevation in products related to the Th1 (including IFN-γ) and Th17 responses, which amplify the migration of neutrophils in the skin. IL-4, a regulator of neutrophil migration, is decreased in chronic AD. NETs continuously supply IL-17 and induce Th17 cells to release more IL-17, leading to T cell polarization in AD. This shift from a Th2-predominant acute phase to a Th1-characterized chronic phase facilitates increased skin neutrophil infiltration and pruritus lichenification. Lastly, neutrophils trigger itch by activating sensory neurons via CXCR3 signaling

Fig. 2

Drugs targeting neutrophils in atopic dermatitis. Several FDA-approved AD drugs or under clinical trials exhibit anti-neutrophilic inflammatory activity. PDE4 inhibitors such as crisaborole and roflumilast inhibit neutrophil chemotaxis. Pan-JAK inhibitors such as delgocitinib, tofacitinib, abrocitinib, ruxolitinib, and baricitinib attenuate respiratory burst and NETs formation in activated neutrophils. Calcineurin inhibitors such as cyclosporine and tacrolimus reduce NETs formation and release of various proinflammatory cytokines. 5-Lipoxygenase inhibitors such as zileuton inhibit adhesion and chemotaxis of neutrophils. Apart from exhibiting antioxidant effects, N-acetylcysteine also ameliorates adhesion and respiratory burst of neutrophils. Vitamin E may inhibit neutrophil chemotaxis