Control of the Physical and Antimicrobial Skin Barrier by an IL-31-IL-1 Signaling Network
Control of the Physical and Antimicrobial Skin Barrier by an IL-31-IL-1 Signaling Network
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DOI：
10.4049/jimmunol.1402943
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发表时间：
2016-04-15
影响因子：
4.4
通讯作者：
Baron, Jens M.
中科院分区：
文献类型：
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作者：
Haenel, Kai H.;Pfaff, Carolina M.;Baron, Jens M.
特应性皮炎是一种慢性炎症性皮肤病，其发病率日益增加，与皮肤屏障缺陷密切相关。与疾病严重程度和角质形成细胞分化的抑制相关的细胞因子是IL-31。为了鉴定其分子靶点，在三维器官型皮肤模型中测定IL-31依赖性基因表达。IL-31调节的基因参与完整的物理皮肤屏障的形成。由于IL-31处理，这些基因中的许多在分化过程中诱导不良，导致对过敏原和刺激物的渗透性增加。此外，在SCID/NOD小鼠中采用细胞分选的皮肤等同物的研究表明，在皮下给药后，给予IL-31。我们鉴定了IL-1细胞因子网络作为IL-31信号传导的下游效应物。阿那白滞素，一种IL-1 R拮抗剂，阻断了IL-31对皮肤分化的作用。除了对物理屏障的影响外，IL-31还刺激了抗菌肽的表达，从而抑制了三维器官型皮肤模型上的细菌生长。这在低剂量的IL-31下已经很明显，不足以干扰物理屏障。总之，这些发现表明IL-31以多种方式影响角质形成细胞分化，并且IL-1细胞因子网络是IL-31信号转导在解除物理皮肤屏障调节中的主要下游效应物。此外，通过干扰IL-31（目前评估的药物靶点），我们必须考虑低剂量的IL-31促进抗菌屏障，因此完全抑制IL-31信号传导可能是不可取的。
Atopic dermatitis, a chronic inflammatory skin disease with increasing prevalence, is closely associated with skin barrier defects. A cytokine related to disease severity and inhibition of keratinocyte differentiation is IL-31. To identify its molecular targets, IL-31-dependent gene expression was determined in three-dimensional organotypic skin models. IL-31-regulated genes are involved in the formation of an intact physical skin barrier. Many of these genes were poorly induced during differentiation as a consequence of IL-31 treatment, resulting in increased penetrability to allergens and irritants. Furthermore, studies employing cell-sorted skin equivalents in SCID/NOD mice demonstrated enhanced transepidermal water loss following s.c. administration of IL-31. We identified the IL-1 cytokine network as a downstream effector of IL-31 signaling. Anakinra, an IL-1R antagonist, blocked the IL-31 effects on skin differentiation. In addition to the effects on the physical barrier, IL-31 stimulated the expression of antimicrobial peptides, thereby inhibiting bacterial growth on the three-dimensional organotypic skin models. This was evident already at low doses of IL-31, insufficient to interfere with the physical barrier. Together, these findings demonstrate that IL-31 affects keratinocyte differentiation in multiple ways and that the IL-1 cytokine network is a major downstream effector of IL-31 signaling in deregulating the physical skin barrier. Moreover, by interfering with IL-31, a currently evaluated drug target, we will have to consider that low doses of IL-31 promote the antimicrobial barrier, and thus a complete inhibition of IL-31 signaling may be undesirable.