Skin microbiome promotes mast cell maturation by triggering stem cell factor production in keratinocytes.
Skin microbiome promotes mast cell maturation by triggering stem cell factor production in keratinocytes.
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DOI：
10.1016/j.jaci.2016.09.019
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发表时间：
2017-04
期刊：
影响因子：
--
通讯作者：
Di Nardo A
中科院分区：
文献类型：
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作者：
Wang Z;Mascarenhas N;Eckmann L;Miyamoto Y;Sun X;Kawakami T;Di Nardo A
肥大细胞（MC）祖细胞离开骨髓，进入循环，并定居在皮肤和其他组织中。它们在组织中的成熟受到周围微环境的影响。我们测试了环境因素在皮肤MC成熟中发挥作用的假设。在用微生物群重建的无菌（GF）、SPF和GF小鼠之间对MC进行数字、表型和功能比较。然后将MC的成熟度与皮肤中干细胞因子（SCF）（一种关键的MC分化因子）和脂磷壁酸（LTA）（一种TLR 2配体）的水平相关。还在具有角质形成细胞特异性Scf缺失的小鼠中评价了MC。我们发现，GF小鼠表达异常低量的干细胞因子（SCF），一个关键的MC分化因子，并含有MC，主要是未分化的。重建GF微生物群使这种MC表型恢复正常，表明该表型与微生物群和皮肤的持续相互作用有关。与GF MC的不成熟一致，引起脱颗粒的化合物48/80在GF小鼠的皮肤中诱导的水肿比在常规小鼠中少。我们的研究结果表明，皮肤微生物组驱动角质形成细胞中的SCF产生，这触发了真皮MC的分化。由于皮肤微生物组是脂磷壁酸（LTA）（一种TLR 2配体）的丰富来源，我们通过将LTA应用于GF小鼠的皮肤来模拟GF微生物组对MC的影响。我们还证明了MC在皮肤内的迁移完全依赖于角质形成细胞产生的SCF。这项研究揭示了一种新的机制，通过这种机制，皮肤微生物群通过LTA刺激的角质形成细胞产生SCF来发出真皮内MC募集和成熟的信号。
Mast cell (MC) progenitors leave the bone marrow, enter the circulation, and settle in the skin and other tissues. Their maturation in tissues is influenced by the surrounding microenvironment. We tested the hypothesis that environmental factors play a role in MC maturation in the skin. MCs were numerically, phenotypically, and functionally compared between germ-free (GF), SPF, and GF mice reconstituted with microbiota. Maturity of MCs was then correlated with skin levels of stem cell factor (SCF), a critical MC differentiation factor, and lipoteichoic acid (LTA), a TLR2 ligand. MCs were also evaluated in mice with keratinocyte-specific deletion of Scf. We found that GF mice express abnormally low amounts of stem cell factor (SCF), a critical MC differentiation factor, and contain MCs that are largely undifferentiated. Reconstituting the GF microbiota reverted this MC phenotype to normal, indicating that the phenotype is related to ongoing interactions of microbiota and skin. Consistent with the immaturity of GF MCs, degranulation-provoking compound 48/80 induced less edema in the skin of GF mice than in conventional mice. Our results show that the skin microbiome drives SCF production in keratinocytes, which triggers the differentiation of dermal MCs. Since the skin microbiome is a rich source of lipoteichoic acid (LTA), a TLR2 ligand, we mimicked the GF microbiome impact on MCs by applying LTA to the skin of GF mice. We also demonstrated that MC migration within the skin depends exclusively on keratinocyte-produced SCF. This study has revealed a novel mechanism by which the skin microbiota signals the recruitment and maturation of MCs within the dermis via SCF production by LTA-stimulated keratinocytes.