HSF1对内毒素血症小鼠多器官损伤的保护作用及其机制
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摘要
脓毒症(sepsis)是由感染引起的全身炎症反应综合征(systemic inflammatory response syndrome,SIRS)。虽然脓毒症的发生机制尚未完全阐明,但是革兰氏阴性细菌胞壁上的脂多糖(lipopolysacchride,LPS)即内毒素启动体内免疫系统在脓毒症发病中的重要性已受到广泛关注。LPS进入机体内可激活多条信号转导通路,启动宿主防御反应,导致大量炎症介质基因的过度表达和全身炎症细胞活化。脓毒症发生机制的核心是感染所引起的失控性炎症反应,其主要特征和机制是过度的中性粒细胞(polymorphonuclear neutrophil,PMN)浸润,引起多器官损伤。
热休克因子1(heat shock factor1,HSF1)是调控热休克反应的关键转录因子。本室前期研究发现HSF1敲除小鼠(HSF1-/-)对LPS的敏感性显著增强和生存率明显降低,表明HSF1对LPS所致的内毒素血症具有保护作用。但是HSF1的保护机制目前仍不清楚。内毒素血症的主要特征和机制是大量中性粒细胞浸润肺、肝和肾等。HSF1是否影响LPS所致内毒素血症的中性粒细胞浸润?目前尚未见报道。
为了探讨HSF1对LPS所致的内毒素血症小鼠的多器官损伤的保护作用和可能机制,本研究第一章采用复制内毒素血症小鼠模型,在整体水平进行一系列组织细胞损伤指标测定和组织学分析。结果发现与野生型(wild type,WT)小鼠相比较,LPS注射4h引起HSF1-/-小鼠释放到血清的炎性介质(IL-6和G-CSF)和器官损伤酶学指标(LDH.BUN和ALT)水平明显升高,肺和肾微血管通透性和湿干比重显著升高。进一步研究发现LPS注射导致HSF1-/-小鼠肺、肝和肾等易感器官的中性粒细胞浸润明显增多,组织损伤更加明显,与LPS引起HSF1-/-小鼠的生存率显著降低相一致。上述结果表明HSF1对LPS诱导的多器官损伤具有保护作用,其机制与抑制过度的中性粒细胞浸润有关。
中性粒细胞浸润是涉及粘附和趋化作用的、受到精细调节的一个多步骤过程。最近,本室利用HSF1-/-和WT小鼠制备内毒素血症模型,采用含384个炎症因子基因的微阵列从内毒素血症小鼠肺组织中筛选HSF1调控的炎症相关基因,首次发现HSF1可能抑制与细胞的粘附和趋化有关的两个分子的表达：即细胞粘附分子P选择素糖蛋白配体(P-selectin glycoprotein ligand1, PSGL-1)和趋化因子受体XCR1。这提示HSF1对LPS所致内毒素血症的中性粒细胞的粘附和趋化作用可能存在抑制作用。
为了探讨HSF1对LPS所致的内毒素血症的中性粒细胞粘附作用的影响及其机制,本研究第二章采用HSF1-/-小鼠复制内毒素血症小鼠模型,运用抗粒细胞染色法在整体水平观察中性粒细胞与血管内皮细胞的粘附作用,发现LPS诱导HSF1-/-小鼠中性粒细胞与血管内皮细胞的粘附比WT小鼠中性粒细胞更强。进一步采用实时定量PCR检测骨髓中性粒细胞的PSGL-1mRNA水平,采用细胞流式术检测用或不用抗PSGL-1单抗处理的内毒素血症小鼠的循环中性粒细胞表面的PSGL-1的蛋白表达水平,采用细胞流式术和免疫组化技术分别检测循环中性粒细胞表面的CD11b和血管内皮细胞表面的ICAM-1表达水平。结果显示,在基础水平,中性粒细胞表面的PSGL-1和CDllb表达水平比较低,而在HSF1-/-小鼠中性粒细胞的表达比WT更高。经LPS刺激后,中性粒细胞表达PSGL-1和CD11b上调,与WT组比,LPS诱导HSF1-/-中性粒细胞表面的PSGL-1和CDllb表达上调更显著。PSGL-1的蛋白表达变化与mRNA水平的变化十分相似。这表明HSF1可下调中性粒细胞表面的PSGL-1和CDllb的组成型表达与LPS所致的诱导型表达。另外,LPS诱导HSF1-/--小鼠的血管内皮细胞表面表达更高的ICAM-1水平。而LPS处理对WT和HSF1-/-中性粒细胞的Hsp70表达没有显著影响。这些结果表明在内毒素血症过程中,HSF1通过抑制中性粒细胞表面的PSGL-1和CDllb的上调以及血管内皮细胞表面的ICAM-1表达,从而抑制LPS所致的中性粒细胞与内皮细胞的粘附。
趋化性是吞噬细胞朝一些浓度递增的趋化物如细菌因子(LPS等)和趋化因子进行定向运动的特性。为了探讨HSF1对中性粒细胞趋化作用的影响及其机制,本研究第三章利用WT和HSF1-/-小鼠骨髓中性粒细胞,采用趋化实验在细胞水平观察两种不同基因型细胞对LPS或肺匀浆的趋化反应,发现HSF1-/-小鼠骨髓中性粒细胞对LPS或内毒素血症小鼠肺匀浆的趋化性比WT小鼠中性粒细胞明显增强。然后复制内毒素血症模型,在整体水平采用ELISA检测血清趋化因子MIP2和XCL1的水平,采用流式细胞术检测循环中性粒细胞表面的CXCR2的表达水平,采用实时定量PCR和细胞免疫荧光技术分别检测中性粒细胞的XCR1mRNA和蛋白表达。结果发现LPS诱导WT和HSF1-/-小鼠循环中性粒细胞的CXCR2表达降低,在LPS注射的WT和HSF1-/-小鼠之间,两组循环中性粒细胞表面的CXCR2表达无明显差异。尽管经LPS注射后,WT和HSF1-/-小鼠血清MIP2水平都显著升高,但在WT和HSF1-/-之间没有明显的差异。然而,内毒素血症时,HSF1-/-小鼠循环中性粒细胞表面的XCR1表达水平和释放到血清的XCL1水平均明显高于WT小鼠。在体外,LPS诱导HSF1-/-小鼠骨髓中性粒细胞的XCR1mRNA和蛋白水平显著增加。且随LPS处理时间的延长,HSF1-/-骨髓中性粒细胞表达的XCR1蛋白递增,而LPS对WT骨髓中性粒细胞的XCR1表达没有明显的影响。值得注意的是,在基础水平,HSF1-/-中性粒细胞的XCR1表达显著低于WT中性粒细胞。其机制目前仍不清楚。上述结果表明HSF1对LPS诱导的中性粒细胞表面的XCR1表达上调具有抑制作用。肌动蛋白细胞骨架和伪足小体形成的变化是迁移细胞的特点。为了明确HSF1-/-是否改变细胞骨架重排,我们研究了WT和HSF1-/-小鼠的循环中性粒细胞和骨髓中性粒细胞的F-actin重组。结果发现LPS诱导小鼠骨髓中性粒细胞形成富含F-actin的板状伪足。与WT小鼠相比,HSF1-/-小鼠骨髓中性粒细胞中显示富含F-actin的范围显著增加,这与HSF1-/-中性粒细胞的趋化性和迁移增强一致。此外,HSF1-/-骨髓中性粒细胞的F-actin聚合随体外LPS处理时间的延长而递增。而一旦用actin聚合的抑制剂即细胞松弛素B破坏F-actin,则WT和HSF1-/-小鼠中性粒细胞对LPS的趋化反应被完全废除。这些结果表明在内毒素血症过程中,HSF1通过抑制中性粒细胞表面的XCR1表达上调和血清趋化因子XCL1的产生,以及抑制LPS诱导的中性粒细胞的F-actin聚合,从而抑制中性粒细胞的趋化和迁移。
此外,在前期工作中我们通过生物信息学分析发现PSGL-1和XCR1基因的启动子区上游均含有一个热休克元件,因此HSF1可能在转录水平直接抑制psgl-1和xcrl基因的表达。
综上所述,本研究首次提出在小鼠内毒素血症过程中,HSF1对LPS诱导的多器官损伤的保护作用与抑制过度的中性粒细胞浸润有关。一方面,HSF1通过抑制LPS诱导的中性粒细胞表面的PSGL-1和CDllb的表达以及血管内皮细胞表面的ICAM-1表达而抑制中性粒细胞与血管内皮细胞的粘附；另一方面,HSF1通过抑制LPS诱导的XCL1产生,和中性粒细胞的XCR1表达以及F-actin聚合,从而抑制中性粒细胞的趋化和迁移。上述发现为揭示脓毒症的发病机制提供了新的实验依据,也为从HSF1角度探讨内毒素血症和脓毒症的防治提供新的思路与实验线索。
Sepsis is a systemic inflammatory response syndrome (SIRS) triggered by infection. Although the mechanisms of sepsis have not yet been fully elucidated, it is well established that lipopolysaccharide (LPS) or endotoxin plays an important role in the pathogenesis of sepsis by initiating the immune system in vivo. LPS can activate several signal transduction pathways and initiate the host defense response, resulting in overexpression of a large number of inflammatory mediators and activation of the systemic inflammatory cells. The key mechanism in the pathogenesis of sepsis is uncontrolled inflammatory response to infection and its main characteristics and mechanisms is excessive neutrophil (polymorphonuclear neutrophil, PMN) infiltration which ultimately results in multiple organ injury.
Heat shock factor1(HSF1) is the major transcriptional factor that regulates the heat shock response. Our previous study found that HSF1knockout mice (HSF1-/-) were more sensitive to LPS; and when treated with LPS, these mice showed lower survival rate. This indicates that HSF1is essential in protection against the systemic inflammation induced by bacterial endotoxin. However, the protective mechanism remains obscure. Although LPS-induced endotoxemia is characterized with infiltration of PMNs in the lungs, liver, and kidneys, whether does HSF1have an effect on PMN infiltration is still unclear.
To explore the protective effect of HSF1on the multiple organ injury in LPS-induced endotoxemia mice and underlying mechanisms, we prepared a mouse model of endotoxemia and measured a series of parameters of tissue injury and performed histology analysis at the overall animal level. The results showed that:1)4h after the injection of LPS, higher level of serum inflammatory mediators such as IL-6and G-CSF, and enzymatic indicators such as LDH, ALT and BUN were observed in HSF1-/-mice than WT mice.2)4h after the injection of LPS and comparing with WT mice, microvascular permeability and wet/dry ratio of lung and renal tissues increased significantly in HSF1-/-mice.3) Consistent with lower survival rate, PMN infiltration and histopathology in multiple susceptible organs (lungs, liver and kidneys) were significantly exacerbated in HSF1-/-mice when treated with LPS, suggesting that HSF1has a protective effect on LPS-induced multiple organ injury, which is associated with the suppression of excessive PMN infiltration.
PMN infiltration is a highly regulated multistep process that involves adhesion and chemotaxis. Recently, we prepared an endotoxemia model to screen HSF1-regulated inflammation-related genes from the lung tissue by microarray with384inflammatory cytokine genes. We found that HSF1may inhibit the expression of P-selectin glycoprotein ligand1(PSGL-1, a cell adhesion molecule) and XCR1(a chemokine receptor), suggesting that HSF1plays a potential inhibitory role in PMN adhesion and chemotaxis in LPS-induced endotoxemia.
Next we decided to explore the effect of HSF1on PMN adhesion in LPS-induced endotoxemia. By anti-granulocyte staining, we demonstrated that PMNs in the HSF1-/-mice after LPS challenge were more adhesive to endothelium than that in the WT mice. Then, the mRNA level of PSGL-1was measured by quantitative real-time PCR, and the protein level of PSGL-1on PMN surface was measured by flow cytometry analysis. The expression levels of CD11b on PMN surface and intercellular adhesion molecule-1(ICAM-1) on endothelium were detected by flow cytometry and immunohistochemical analysis, respectively. We found that the protein levels of PSGL-1and CD11b on HSF1-/-PMNs at baseline were higher than that of the WT PMNs. LPS induced the surface expression of PSGL-1and CD11b on the PMNs of WT and HSF1-/-mice. However, greater surface expression of PSGL-1and CD11b was shown on the PMN surface of HSF1-/-mice after LPS treatment. These results indicate that HSF1is capable of down-regulating both constitutive and inducible expressions of PSGL-1and CDllb on PMNs. In addition, LPS induced higher level of ICAM-1expression on the endothelium of HSF1-/-mice. Nevertheless, the effect of LPS treatment on Hsp70protein levels in PMNs of WT and HSF1-/-mice is minimal. These results suggest that HSF1inhibits PMN adhension to endothelium by suppressing the surface expression of PSGL-1and CD11b on PMNs as well as ICAM-1on endothelium during endotoxemia.
Chemotaxis is the movement of phagocytes toward an increasing concentration of attractants such as bacterial factors (LPS etc.) and chemokines. To explore the effect of HSF1on PMN chemotaxis and its mechanisms, chemotactic chamber assay was conducted to evaluate the migratory capacity of WT and HSF1-/-BM PMNs to multiple migration-inducing stimuli, including LPS (0.6μg/ml) and lung homogenates from endotoxemia mice. We found that the chemotactic activities of PMNs from the HSF1-/-mice were significantly higher than that from the WT mice. The levels of serum MIP2and XCL1were measured by ELISA. CXCR2expression on PMN surface was detected by flow cytometry analysis. The mRNA level of XCR1in BM PMNs was measured by quantitative real-time PCR. The protein expression of XCR1on circulating PMNs or BM PMNs was evaluated by immunocytochemical analysis. It was found that LPS reduced CXCR2expression on PMNs from WT and HSF11-/-mice. However, the differences in CXCR2expression on circulating PMN of the WT and HSF1-/-mice after LPS injection were negligible. There was no significant difference between serum MIP2production of the WT and the HSF1-/-mice at basal levels or after LPS exposure, although the levels of serum MIP2significantly increased in WT and HSF1-/-mice after LPS treatment. However, LPS induced higher level of serum XCL1in HSF1-/-mice and greater surface expression of XCR1on circulating PMN of the HSF1-/-mice. LPS induced a marked increase in both mRNA and protein level of XCR1in PMNs of HSF1-/-, but not WT mice. XCR1expression on HSF1-/-BM PMNs increased progressively during the in vitro LPS treatment, and this effect was not observed in the WT BM PMNs. Notably, the basal expression of XCR1on HSF1-/-PMNs was lower than that on WT PMNs. This suggests an inhibitory role of HSF1in LPS-induced XCR1expression on PMNs. Changes in cytoskeleton and podosome formation are hallmarks of migrating cells. To determine whether HSF1-/-alters cytoskeleton rearrangement, F-actin reorganization was examined in circulating and BM PMNs from WT and HSF1-/-mice. Formation of lamellipodia in response to LPS was seen in the WT BM PMNs, whereas HSF1-/-cells displayed a significant increase in F-actin-rich extensions. This is in consistent with enhanced chemotaxis and migration in HSF1-/-BM PMNs. Moreover, F-actin polymerization in HSF1-/-BM PMNs increased progressively during the in vitro LPS treatment. Once F-actin was disrupted by cytochalasin B, an inhibitor of actin polymerization, the chemotactic response of WT and HSF1-/-BM PMNs to LPS was shown to be completely abolished, indicating that HSF1inhibits LPS-induced F-actin polymerization in PMNs. These results suggest that HSF1inhibits PMN chemotaxis and migration by suppressing the surface expression of XCR1on PMN and serum XCL1production, as well as F-actin polymerization in PMN during endotoxemia.
Previously, our bioinformatic analysis found a heat shock element located at the upstream of the transcription starting sites of the psgl-1and xcr1genes. Therefore, as a transcription factor, HSF1may repress psgl-1and xcr1directly at the transcriptional level.
In summary, this study demonstrated for the first time that, the protective role of HSF1in LPS-induced multiple organ injury is related to the suppression of excessive PMN infiltration. Mechanistically, during endotoxemia,1) HSF1inhibits PMN adhesion to vascular endothelial cells by suppressing the expression of LPS-induced PSGL-1and CD11b on PMN surface and ICAM-1on vascular endothelial cell surface;2) HSF1inhibits PMN chemotaxis and migration by suppressing XCL1production, the XCR1receptor expression and F-actin polymerization in PMN. This study has provided not only a novel model for the pathogenesis of sepsis, but also new ideas and clues for the prevention and treatment of endotoxemia and sepsis.
热休克因子1(heat shock factor1,HSF1)是调控热休克反应的关键转录因子。本室前期研究发现HSF1敲除小鼠(HSF1-/-)对LPS的敏感性显著增强和生存率明显降低,表明HSF1对LPS所致的内毒素血症具有保护作用。但是HSF1的保护机制目前仍不清楚。内毒素血症的主要特征和机制是大量中性粒细胞浸润肺、肝和肾等。HSF1是否影响LPS所致内毒素血症的中性粒细胞浸润?目前尚未见报道。
为了探讨HSF1对LPS所致的内毒素血症小鼠的多器官损伤的保护作用和可能机制,本研究第一章采用复制内毒素血症小鼠模型,在整体水平进行一系列组织细胞损伤指标测定和组织学分析。结果发现与野生型(wild type,WT)小鼠相比较,LPS注射4h引起HSF1-/-小鼠释放到血清的炎性介质(IL-6和G-CSF)和器官损伤酶学指标(LDH.BUN和ALT)水平明显升高,肺和肾微血管通透性和湿干比重显著升高。进一步研究发现LPS注射导致HSF1-/-小鼠肺、肝和肾等易感器官的中性粒细胞浸润明显增多,组织损伤更加明显,与LPS引起HSF1-/-小鼠的生存率显著降低相一致。上述结果表明HSF1对LPS诱导的多器官损伤具有保护作用,其机制与抑制过度的中性粒细胞浸润有关。
中性粒细胞浸润是涉及粘附和趋化作用的、受到精细调节的一个多步骤过程。最近,本室利用HSF1-/-和WT小鼠制备内毒素血症模型,采用含384个炎症因子基因的微阵列从内毒素血症小鼠肺组织中筛选HSF1调控的炎症相关基因,首次发现HSF1可能抑制与细胞的粘附和趋化有关的两个分子的表达：即细胞粘附分子P选择素糖蛋白配体(P-selectin glycoprotein ligand1, PSGL-1)和趋化因子受体XCR1。这提示HSF1对LPS所致内毒素血症的中性粒细胞的粘附和趋化作用可能存在抑制作用。
为了探讨HSF1对LPS所致的内毒素血症的中性粒细胞粘附作用的影响及其机制,本研究第二章采用HSF1-/-小鼠复制内毒素血症小鼠模型,运用抗粒细胞染色法在整体水平观察中性粒细胞与血管内皮细胞的粘附作用,发现LPS诱导HSF1-/-小鼠中性粒细胞与血管内皮细胞的粘附比WT小鼠中性粒细胞更强。进一步采用实时定量PCR检测骨髓中性粒细胞的PSGL-1mRNA水平,采用细胞流式术检测用或不用抗PSGL-1单抗处理的内毒素血症小鼠的循环中性粒细胞表面的PSGL-1的蛋白表达水平,采用细胞流式术和免疫组化技术分别检测循环中性粒细胞表面的CD11b和血管内皮细胞表面的ICAM-1表达水平。结果显示,在基础水平,中性粒细胞表面的PSGL-1和CDllb表达水平比较低,而在HSF1-/-小鼠中性粒细胞的表达比WT更高。经LPS刺激后,中性粒细胞表达PSGL-1和CD11b上调,与WT组比,LPS诱导HSF1-/-中性粒细胞表面的PSGL-1和CDllb表达上调更显著。PSGL-1的蛋白表达变化与mRNA水平的变化十分相似。这表明HSF1可下调中性粒细胞表面的PSGL-1和CDllb的组成型表达与LPS所致的诱导型表达。另外,LPS诱导HSF1-/--小鼠的血管内皮细胞表面表达更高的ICAM-1水平。而LPS处理对WT和HSF1-/-中性粒细胞的Hsp70表达没有显著影响。这些结果表明在内毒素血症过程中,HSF1通过抑制中性粒细胞表面的PSGL-1和CDllb的上调以及血管内皮细胞表面的ICAM-1表达,从而抑制LPS所致的中性粒细胞与内皮细胞的粘附。
趋化性是吞噬细胞朝一些浓度递增的趋化物如细菌因子(LPS等)和趋化因子进行定向运动的特性。为了探讨HSF1对中性粒细胞趋化作用的影响及其机制,本研究第三章利用WT和HSF1-/-小鼠骨髓中性粒细胞,采用趋化实验在细胞水平观察两种不同基因型细胞对LPS或肺匀浆的趋化反应,发现HSF1-/-小鼠骨髓中性粒细胞对LPS或内毒素血症小鼠肺匀浆的趋化性比WT小鼠中性粒细胞明显增强。然后复制内毒素血症模型,在整体水平采用ELISA检测血清趋化因子MIP2和XCL1的水平,采用流式细胞术检测循环中性粒细胞表面的CXCR2的表达水平,采用实时定量PCR和细胞免疫荧光技术分别检测中性粒细胞的XCR1mRNA和蛋白表达。结果发现LPS诱导WT和HSF1-/-小鼠循环中性粒细胞的CXCR2表达降低,在LPS注射的WT和HSF1-/-小鼠之间,两组循环中性粒细胞表面的CXCR2表达无明显差异。尽管经LPS注射后,WT和HSF1-/-小鼠血清MIP2水平都显著升高,但在WT和HSF1-/-之间没有明显的差异。然而,内毒素血症时,HSF1-/-小鼠循环中性粒细胞表面的XCR1表达水平和释放到血清的XCL1水平均明显高于WT小鼠。在体外,LPS诱导HSF1-/-小鼠骨髓中性粒细胞的XCR1mRNA和蛋白水平显著增加。且随LPS处理时间的延长,HSF1-/-骨髓中性粒细胞表达的XCR1蛋白递增,而LPS对WT骨髓中性粒细胞的XCR1表达没有明显的影响。值得注意的是,在基础水平,HSF1-/-中性粒细胞的XCR1表达显著低于WT中性粒细胞。其机制目前仍不清楚。上述结果表明HSF1对LPS诱导的中性粒细胞表面的XCR1表达上调具有抑制作用。肌动蛋白细胞骨架和伪足小体形成的变化是迁移细胞的特点。为了明确HSF1-/-是否改变细胞骨架重排,我们研究了WT和HSF1-/-小鼠的循环中性粒细胞和骨髓中性粒细胞的F-actin重组。结果发现LPS诱导小鼠骨髓中性粒细胞形成富含F-actin的板状伪足。与WT小鼠相比,HSF1-/-小鼠骨髓中性粒细胞中显示富含F-actin的范围显著增加,这与HSF1-/-中性粒细胞的趋化性和迁移增强一致。此外,HSF1-/-骨髓中性粒细胞的F-actin聚合随体外LPS处理时间的延长而递增。而一旦用actin聚合的抑制剂即细胞松弛素B破坏F-actin,则WT和HSF1-/-小鼠中性粒细胞对LPS的趋化反应被完全废除。这些结果表明在内毒素血症过程中,HSF1通过抑制中性粒细胞表面的XCR1表达上调和血清趋化因子XCL1的产生,以及抑制LPS诱导的中性粒细胞的F-actin聚合,从而抑制中性粒细胞的趋化和迁移。
此外,在前期工作中我们通过生物信息学分析发现PSGL-1和XCR1基因的启动子区上游均含有一个热休克元件,因此HSF1可能在转录水平直接抑制psgl-1和xcrl基因的表达。
综上所述,本研究首次提出在小鼠内毒素血症过程中,HSF1对LPS诱导的多器官损伤的保护作用与抑制过度的中性粒细胞浸润有关。一方面,HSF1通过抑制LPS诱导的中性粒细胞表面的PSGL-1和CDllb的表达以及血管内皮细胞表面的ICAM-1表达而抑制中性粒细胞与血管内皮细胞的粘附；另一方面,HSF1通过抑制LPS诱导的XCL1产生,和中性粒细胞的XCR1表达以及F-actin聚合,从而抑制中性粒细胞的趋化和迁移。上述发现为揭示脓毒症的发病机制提供了新的实验依据,也为从HSF1角度探讨内毒素血症和脓毒症的防治提供新的思路与实验线索。
Sepsis is a systemic inflammatory response syndrome (SIRS) triggered by infection. Although the mechanisms of sepsis have not yet been fully elucidated, it is well established that lipopolysaccharide (LPS) or endotoxin plays an important role in the pathogenesis of sepsis by initiating the immune system in vivo. LPS can activate several signal transduction pathways and initiate the host defense response, resulting in overexpression of a large number of inflammatory mediators and activation of the systemic inflammatory cells. The key mechanism in the pathogenesis of sepsis is uncontrolled inflammatory response to infection and its main characteristics and mechanisms is excessive neutrophil (polymorphonuclear neutrophil, PMN) infiltration which ultimately results in multiple organ injury.
Heat shock factor1(HSF1) is the major transcriptional factor that regulates the heat shock response. Our previous study found that HSF1knockout mice (HSF1-/-) were more sensitive to LPS; and when treated with LPS, these mice showed lower survival rate. This indicates that HSF1is essential in protection against the systemic inflammation induced by bacterial endotoxin. However, the protective mechanism remains obscure. Although LPS-induced endotoxemia is characterized with infiltration of PMNs in the lungs, liver, and kidneys, whether does HSF1have an effect on PMN infiltration is still unclear.
To explore the protective effect of HSF1on the multiple organ injury in LPS-induced endotoxemia mice and underlying mechanisms, we prepared a mouse model of endotoxemia and measured a series of parameters of tissue injury and performed histology analysis at the overall animal level. The results showed that:1)4h after the injection of LPS, higher level of serum inflammatory mediators such as IL-6and G-CSF, and enzymatic indicators such as LDH, ALT and BUN were observed in HSF1-/-mice than WT mice.2)4h after the injection of LPS and comparing with WT mice, microvascular permeability and wet/dry ratio of lung and renal tissues increased significantly in HSF1-/-mice.3) Consistent with lower survival rate, PMN infiltration and histopathology in multiple susceptible organs (lungs, liver and kidneys) were significantly exacerbated in HSF1-/-mice when treated with LPS, suggesting that HSF1has a protective effect on LPS-induced multiple organ injury, which is associated with the suppression of excessive PMN infiltration.
PMN infiltration is a highly regulated multistep process that involves adhesion and chemotaxis. Recently, we prepared an endotoxemia model to screen HSF1-regulated inflammation-related genes from the lung tissue by microarray with384inflammatory cytokine genes. We found that HSF1may inhibit the expression of P-selectin glycoprotein ligand1(PSGL-1, a cell adhesion molecule) and XCR1(a chemokine receptor), suggesting that HSF1plays a potential inhibitory role in PMN adhesion and chemotaxis in LPS-induced endotoxemia.
Next we decided to explore the effect of HSF1on PMN adhesion in LPS-induced endotoxemia. By anti-granulocyte staining, we demonstrated that PMNs in the HSF1-/-mice after LPS challenge were more adhesive to endothelium than that in the WT mice. Then, the mRNA level of PSGL-1was measured by quantitative real-time PCR, and the protein level of PSGL-1on PMN surface was measured by flow cytometry analysis. The expression levels of CD11b on PMN surface and intercellular adhesion molecule-1(ICAM-1) on endothelium were detected by flow cytometry and immunohistochemical analysis, respectively. We found that the protein levels of PSGL-1and CD11b on HSF1-/-PMNs at baseline were higher than that of the WT PMNs. LPS induced the surface expression of PSGL-1and CD11b on the PMNs of WT and HSF1-/-mice. However, greater surface expression of PSGL-1and CD11b was shown on the PMN surface of HSF1-/-mice after LPS treatment. These results indicate that HSF1is capable of down-regulating both constitutive and inducible expressions of PSGL-1and CDllb on PMNs. In addition, LPS induced higher level of ICAM-1expression on the endothelium of HSF1-/-mice. Nevertheless, the effect of LPS treatment on Hsp70protein levels in PMNs of WT and HSF1-/-mice is minimal. These results suggest that HSF1inhibits PMN adhension to endothelium by suppressing the surface expression of PSGL-1and CD11b on PMNs as well as ICAM-1on endothelium during endotoxemia.
Chemotaxis is the movement of phagocytes toward an increasing concentration of attractants such as bacterial factors (LPS etc.) and chemokines. To explore the effect of HSF1on PMN chemotaxis and its mechanisms, chemotactic chamber assay was conducted to evaluate the migratory capacity of WT and HSF1-/-BM PMNs to multiple migration-inducing stimuli, including LPS (0.6μg/ml) and lung homogenates from endotoxemia mice. We found that the chemotactic activities of PMNs from the HSF1-/-mice were significantly higher than that from the WT mice. The levels of serum MIP2and XCL1were measured by ELISA. CXCR2expression on PMN surface was detected by flow cytometry analysis. The mRNA level of XCR1in BM PMNs was measured by quantitative real-time PCR. The protein expression of XCR1on circulating PMNs or BM PMNs was evaluated by immunocytochemical analysis. It was found that LPS reduced CXCR2expression on PMNs from WT and HSF11-/-mice. However, the differences in CXCR2expression on circulating PMN of the WT and HSF1-/-mice after LPS injection were negligible. There was no significant difference between serum MIP2production of the WT and the HSF1-/-mice at basal levels or after LPS exposure, although the levels of serum MIP2significantly increased in WT and HSF1-/-mice after LPS treatment. However, LPS induced higher level of serum XCL1in HSF1-/-mice and greater surface expression of XCR1on circulating PMN of the HSF1-/-mice. LPS induced a marked increase in both mRNA and protein level of XCR1in PMNs of HSF1-/-, but not WT mice. XCR1expression on HSF1-/-BM PMNs increased progressively during the in vitro LPS treatment, and this effect was not observed in the WT BM PMNs. Notably, the basal expression of XCR1on HSF1-/-PMNs was lower than that on WT PMNs. This suggests an inhibitory role of HSF1in LPS-induced XCR1expression on PMNs. Changes in cytoskeleton and podosome formation are hallmarks of migrating cells. To determine whether HSF1-/-alters cytoskeleton rearrangement, F-actin reorganization was examined in circulating and BM PMNs from WT and HSF1-/-mice. Formation of lamellipodia in response to LPS was seen in the WT BM PMNs, whereas HSF1-/-cells displayed a significant increase in F-actin-rich extensions. This is in consistent with enhanced chemotaxis and migration in HSF1-/-BM PMNs. Moreover, F-actin polymerization in HSF1-/-BM PMNs increased progressively during the in vitro LPS treatment. Once F-actin was disrupted by cytochalasin B, an inhibitor of actin polymerization, the chemotactic response of WT and HSF1-/-BM PMNs to LPS was shown to be completely abolished, indicating that HSF1inhibits LPS-induced F-actin polymerization in PMNs. These results suggest that HSF1inhibits PMN chemotaxis and migration by suppressing the surface expression of XCR1on PMN and serum XCL1production, as well as F-actin polymerization in PMN during endotoxemia.
Previously, our bioinformatic analysis found a heat shock element located at the upstream of the transcription starting sites of the psgl-1and xcr1genes. Therefore, as a transcription factor, HSF1may repress psgl-1and xcr1directly at the transcriptional level.
In summary, this study demonstrated for the first time that, the protective role of HSF1in LPS-induced multiple organ injury is related to the suppression of excessive PMN infiltration. Mechanistically, during endotoxemia,1) HSF1inhibits PMN adhesion to vascular endothelial cells by suppressing the expression of LPS-induced PSGL-1and CD11b on PMN surface and ICAM-1on vascular endothelial cell surface;2) HSF1inhibits PMN chemotaxis and migration by suppressing XCL1production, the XCR1receptor expression and F-actin polymerization in PMN. This study has provided not only a novel model for the pathogenesis of sepsis, but also new ideas and clues for the prevention and treatment of endotoxemia and sepsis.
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