表皮葡萄球菌脂肽抑制伤口病原微生物感染和调节炎症应答的分子免疫学机制
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摘要
作为机体的第一道屏障,皮肤表面生存着多种微生物。这些微生物大部分是无害的,在一定条件还可以调节机体免疫应答有益于宿主,因此研究皮肤微生物与宿主之间的关系具有重要的意义。表皮葡萄球菌是寄居在皮肤表面的主要共生菌,我们实验室前期研究表明表皮葡萄球菌在增强皮肤免疫防御和调节炎症中具有重要功能,但是对表皮葡萄球菌调节宿主免疫应答的具体活性物质及相应的分子调节机制还不清楚。本文在表皮葡萄球菌发酵液中提取到一种脂肽,其多肽序列为DⅡSTIGDLVKWⅡDTVⅡD ATE,脂肪酸序列为C20H40COOH,脂肪酸结合在多肽的LysⅡ(LP01)或Asp1(LP78)上,这两种脂肽在调节机体先天免疫中具有重要功能。
体外实验证明LP01显著地诱导角质形成细胞中β-防御素的表达,经LP01刺激的角质形成细胞裂解液能够特异性抑制金黄色葡萄球菌的生长；而体内实验进一步证明LP01诱导小鼠β-防御素的表达进而抑制金黄色葡萄球菌对小鼠皮肤的感染,同时小鼠肝脏内金黄色葡萄球菌的数目显著减少,但是脾脏内细菌数目没有改变。本研究进一步探究了LP01诱导p-防御素表达的机制。实验结果显示：TLR2基因被沉默或敲除后,LP01不能诱导β-防御素的表达,也不能抑制金黄色葡萄球菌的生长；CD36基因被沉默后,LP01对p-防御素的诱导作用明显降低；p38MAPK抑制剂SB202190能够显著抑制LP01诱导的β-防御素的表达,因此LP01通过激活TLR2/CD36-p38MAPK信号通路诱导β-防御素的表达。
脂肽除了增强机体免疫防御外还可以调节炎症反应,本研究检测了LP01及其同分异构体LP78对炎症反应的影响,发现LP78抑制poly(I:C)秀导的炎症反应,而LP01本身不能抑制炎症因子的表达。poly(I:C)诱导p65的磷酸化进而促使其入核,p65与PPARγ相结合共同起始炎症反应。LP78能够诱导β-catenin的磷酸化,促使其稳定性和在细胞核内的聚集,β-catenin与p65竞争性地结合PPARγ进而抑制poly(I:C)诱导炎症反应。而LP78调节β-catenin与p65竞争性地结合PPARy是通过激活TLR2/CD14/CD36-PKA信号通路,因为不管是抑制或敲除TLR2,还是将TLR2的辅助受体CD14和CD36基因沉默或PKA活性被抑制后,LP78均不能诱导β-catenin的磷酸化和β-catenin在细胞核内的聚集,从而不能抑制poly(I:C)诱导的炎症反应。而脂肽LP78的生理功能体现在抑制糖尿病小鼠伤口过度的炎症因子的表达从而促进伤口愈合。
总之,表皮葡萄球菌与宿主之间存在着有益的关系,表皮葡萄球菌分泌的脂肽一方面通过激活TLR2/CD36-p38MAPK信号通路诱导防御素的表达抵制病原菌对机体的感染,另一方面通过TLR2/CD14/36-PKA-β-catenin信号通路调节伤口炎症应答进而促进伤口愈合。
As the first barrier of the host, skin is colonized by a diverse collection of microbia. Most of these microbia have benigh relationship with hosts and in some cases provide vital functions that are not evolved by human genome.Therefore, it's important to investigate how skin commensals benefit the host.Our previous work shows that skin commensal bacterium Staphylococcus epidermidis, a gram-positive bacteria, has important roles in enhancing innate immune defense and regulating inflammatory responses. However, the identity of the molecule from S.epidermidis to rugulate skin immunity and the corresponding molecular mechanisms remain unknown. Here I isolated lipopeptides from S.epidermidis cell culture media and these peptides have a unique structure with heneicosanoic acid (C20H41COOH) binding to Lysine11(LP01) or Asp1(LP78) of a peptide chain(DIISTIGDLVKWIIDTVIIDATE). We further showed that these lipopeptides play important roles in the regulation of innate immunity.
Our data show that in vitro LP01(DIISTlGDLVKWIIDTVIIDATE) increased the expression of β-defensin2(hBD2) and hBD3in neonatal human epidermal keratinocytes (NHEKs), leading to increased capacity of cell lysates to inhibit the growth of S.aureus. In vivo LP01induced the expression of mouse β-defensin4(mBD4) to decrease the survival of local S.aureus in skin and systemic S.aureus survival in liver. The induction of beta-defensins by LP01was dependent on TLR2as Tlr2-deficient mice had decreased mBD4. Furthermore, knockdown of CD36decreased the expression of hBD2and hBD3, and p38MAPK inhibitor significantly inhibited the expression of hBDs and p38phosphorylation induced by LP01. We also found that one isomer named LP78) of LP01inhibited poly(I:C)-induced inflammation in vitro and in vivo. poly(I:C) induced p65nuclear translocation to interact with PPARy, thus initiating inflammatory response. LP78induced β-catenin translocation into nucleus to compete with poly(I:C)-induced p65to interact with PPARy, thus inhibiting inflammatory response. The anti-inflammatory effects of LP78was depended on TLR2-CD14/CD36-PKA as LP78did not inhibit inflammation in Tlr2-deficient mice,or lost its capacity to inhibit inflammatory respose after CD14/CD36was knocked down. Furthermore, PKA inhibitor blocked the inhibitory effect of LP78on TLR3-dependent inflammation. The physilogical relevance of LP78in vivo was that LP78reduced excessive inflammatory responses in ulcer wounds, thus promoting wound healing in diabetic mice.
In conclution, these findings demonstrate that S.epidermidis has a benign relationship with the host. In one hand S.epidermidis produces lipopeptide to enhance antibacterial defense against bacterial infection via the activation of TLR2/CD36-p38MAPK. On the other hand, the lipopeptide activates TLR2-CD14/36-PKA-β-catenin signal pathway to regulate inflammatory responses, thus promoting wound healing.
体外实验证明LP01显著地诱导角质形成细胞中β-防御素的表达,经LP01刺激的角质形成细胞裂解液能够特异性抑制金黄色葡萄球菌的生长；而体内实验进一步证明LP01诱导小鼠β-防御素的表达进而抑制金黄色葡萄球菌对小鼠皮肤的感染,同时小鼠肝脏内金黄色葡萄球菌的数目显著减少,但是脾脏内细菌数目没有改变。本研究进一步探究了LP01诱导p-防御素表达的机制。实验结果显示：TLR2基因被沉默或敲除后,LP01不能诱导β-防御素的表达,也不能抑制金黄色葡萄球菌的生长；CD36基因被沉默后,LP01对p-防御素的诱导作用明显降低；p38MAPK抑制剂SB202190能够显著抑制LP01诱导的β-防御素的表达,因此LP01通过激活TLR2/CD36-p38MAPK信号通路诱导β-防御素的表达。
脂肽除了增强机体免疫防御外还可以调节炎症反应,本研究检测了LP01及其同分异构体LP78对炎症反应的影响,发现LP78抑制poly(I:C)秀导的炎症反应,而LP01本身不能抑制炎症因子的表达。poly(I:C)诱导p65的磷酸化进而促使其入核,p65与PPARγ相结合共同起始炎症反应。LP78能够诱导β-catenin的磷酸化,促使其稳定性和在细胞核内的聚集,β-catenin与p65竞争性地结合PPARγ进而抑制poly(I:C)诱导炎症反应。而LP78调节β-catenin与p65竞争性地结合PPARy是通过激活TLR2/CD14/CD36-PKA信号通路,因为不管是抑制或敲除TLR2,还是将TLR2的辅助受体CD14和CD36基因沉默或PKA活性被抑制后,LP78均不能诱导β-catenin的磷酸化和β-catenin在细胞核内的聚集,从而不能抑制poly(I:C)诱导的炎症反应。而脂肽LP78的生理功能体现在抑制糖尿病小鼠伤口过度的炎症因子的表达从而促进伤口愈合。
总之,表皮葡萄球菌与宿主之间存在着有益的关系,表皮葡萄球菌分泌的脂肽一方面通过激活TLR2/CD36-p38MAPK信号通路诱导防御素的表达抵制病原菌对机体的感染,另一方面通过TLR2/CD14/36-PKA-β-catenin信号通路调节伤口炎症应答进而促进伤口愈合。
As the first barrier of the host, skin is colonized by a diverse collection of microbia. Most of these microbia have benigh relationship with hosts and in some cases provide vital functions that are not evolved by human genome.Therefore, it's important to investigate how skin commensals benefit the host.Our previous work shows that skin commensal bacterium Staphylococcus epidermidis, a gram-positive bacteria, has important roles in enhancing innate immune defense and regulating inflammatory responses. However, the identity of the molecule from S.epidermidis to rugulate skin immunity and the corresponding molecular mechanisms remain unknown. Here I isolated lipopeptides from S.epidermidis cell culture media and these peptides have a unique structure with heneicosanoic acid (C20H41COOH) binding to Lysine11(LP01) or Asp1(LP78) of a peptide chain(DIISTIGDLVKWIIDTVIIDATE). We further showed that these lipopeptides play important roles in the regulation of innate immunity.
Our data show that in vitro LP01(DIISTlGDLVKWIIDTVIIDATE) increased the expression of β-defensin2(hBD2) and hBD3in neonatal human epidermal keratinocytes (NHEKs), leading to increased capacity of cell lysates to inhibit the growth of S.aureus. In vivo LP01induced the expression of mouse β-defensin4(mBD4) to decrease the survival of local S.aureus in skin and systemic S.aureus survival in liver. The induction of beta-defensins by LP01was dependent on TLR2as Tlr2-deficient mice had decreased mBD4. Furthermore, knockdown of CD36decreased the expression of hBD2and hBD3, and p38MAPK inhibitor significantly inhibited the expression of hBDs and p38phosphorylation induced by LP01. We also found that one isomer named LP78) of LP01inhibited poly(I:C)-induced inflammation in vitro and in vivo. poly(I:C) induced p65nuclear translocation to interact with PPARy, thus initiating inflammatory response. LP78induced β-catenin translocation into nucleus to compete with poly(I:C)-induced p65to interact with PPARy, thus inhibiting inflammatory response. The anti-inflammatory effects of LP78was depended on TLR2-CD14/CD36-PKA as LP78did not inhibit inflammation in Tlr2-deficient mice,or lost its capacity to inhibit inflammatory respose after CD14/CD36was knocked down. Furthermore, PKA inhibitor blocked the inhibitory effect of LP78on TLR3-dependent inflammation. The physilogical relevance of LP78in vivo was that LP78reduced excessive inflammatory responses in ulcer wounds, thus promoting wound healing in diabetic mice.
In conclution, these findings demonstrate that S.epidermidis has a benign relationship with the host. In one hand S.epidermidis produces lipopeptide to enhance antibacterial defense against bacterial infection via the activation of TLR2/CD36-p38MAPK. On the other hand, the lipopeptide activates TLR2-CD14/36-PKA-β-catenin signal pathway to regulate inflammatory responses, thus promoting wound healing.
引文
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