Interplay between CXCR2 and BLT1 Facilitates Neutrophil Infiltration and Resultant Keratinocyte Activation in a Murine Model of Imiquimod-Induced Psoriasis
Interplay between CXCR2 and BLT1 Facilitates Neutrophil Infiltration and Resultant Keratinocyte Activation in a Murine Model of Imiquimod-Induced Psoriasis
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DOI：
10.4049/jimmunol.1302959
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发表时间：
2014-05-01
影响因子：
4.4
通讯作者：
Shimizu, Takao
中科院分区：
文献类型：
--
作者：
Sumida, Hayakazu;Yanagida, Keisuke;Shimizu, Takao
牛皮癣是一种炎症性皮肤病与加速表皮细胞的更新。皮肤中性粒细胞积聚是银屑病的组织学特征之一。然而，中性粒细胞浸润的确切机制和作用在很大程度上仍然未知。在本文中，我们发现CXCR2和白三烯B4受体BLT1的协同作用在咪喹莫特（IMQ）诱导的小鼠银屑病皮损发展过程中中性粒细胞募集中起关键作用。用抗ly - 6g抗体消耗中性粒细胞可改善疾病的严重程度，同时降低皮肤中促炎细胞因子IL-1 β的表达。此外，在imq诱导的炎症早期，CXCR2和BLT1协同促进中性粒细胞向皮肤的浸润。在体外，CXCR2配体增加小鼠中性粒细胞产生白三烯B4，这反过来又通过自分泌和/或旁分泌方式通过BLT1放大趋化因子介导的中性粒细胞趋化性。与imq处理小鼠皮肤中IL-1 β表达增加一致，IL-1 β显著上调人角质形成细胞中诱导棘层增生的细胞因子IL-1 β的表达。我们提出，趋化因子、脂质和细胞因子与多个正反馈回路的协调可能驱动牛皮癣的发病机制，也可能驱动其他炎症性疾病的发病机制。对这种正反馈或其下游效应的干扰可能是新型抗炎治疗的目标。
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 B4 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-1 beta 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 B4 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-1 beta expression in IMQ-treated mouse skin, IL-1 beta markedly upregulated expression of acanthosis-inducing cytokine IL-1 beta 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.