Murine Model of Imiquimod-Induced Resultant Keratinocyte Activation in a Facilitates Neutrophil Infiltration and Interplay between CXCR2 and BLT1

Psoriasis is an inflammatory skin disease with accelerated epidermal cell turnover. Neutrophil accumulation in the skin is one of the histological characteristics of psoriasis. However, the precise mechanism and role of neutrophil infiltration remain largely unknown. In this article, we show that orchestrated action of CXCR2 and leukotriene B 4 receptor BLT1 plays a key role in neutrophil recruitment during the development of imiquimod (IMQ)-induced psoriatic skin lesions in mice. Depletion of neutrophils with anti–Ly-6G Ab ameliorated the disease severity, along with reduced expression of proinflammatory cytokine IL-1b in the skin. Furthermore, CXCR2 and BLT1 coordinately promote neutrophil infiltration into the skin during the early phase of IMQ-induced inflammation. In vitro, CXCR2 ligands augment leukotriene B 4 production by murine neutrophils, which, in turn, amplifies chemokine-mediated neutrophil chemotaxis via BLT1 in autocrine and/or paracrine manners. In agreement with the increased IL-19 expression in IMQ-treated mouse skin, IL-1b markedly upregulated expression of acanthosis-inducing cyto-kine IL-19 in human keratinocytes. We propose that coordination of chemokines, lipids, and cytokines with multiple positive feedback loops might drive the pathogenesis of psoriasis and, possibly, other inflammatory diseases as well. Interference to this positive feedback or its downstream effectors could be targets of novel anti-inflammatory treatment. P soriasis is a persistent inflammatory skin disease thought to arise as a result of infiltration of inflammatory cells and activation of keratinocytes. Psoriasis has been considered as a classical type 1 autoimmune disease; recently, however, Th17 cells are attracting much interest. Biological drugs targeting the IL-23/IL-17 pathway achieved successful outcomes in psoriasis patients (1). Moreover, a massive amount of neutrophils and activated T cells infiltrates into psoriatic plaques (1). A role for IL-17 in neutrophil-mediated inflammation (2) suggests that neutrophils may also participate in the pathogenesis of psoriasis. Neutrophils have been traditionally considered as an effector arm of innate immunity. However, recent studies suggest an intimate association of neutrophils with acquired immunity (3), suggesting a crucial role of neutrophils in the pathogenesis of a wide variety of diseases, including infections, autoimmunity, chronic inflammation, and cancer (4). In fact, various neutrophil chemoattractants are known to have unique functions in a number of human diseases (5). In psoriasis, neutrophils first infiltrate into the dermis at the early phase and later into the epidermis at the chronic phase (6). Moreover, neutrophil chemoattractants, including CXCL1, CXCL8 (also known as IL-8), and leukotriene B 4 (LTB 4), are upregulated in psoriatic skin (7, 8). …