PD-1对巨噬/小胶质细胞极化的作用机制及其在脊髓损伤修复中的作用研究
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摘要
全世界有超过250万人受到脊髓损伤(spinal cord injury，SCI)，并且以每年13万的例数在增加[1]。SCI所导致的感觉、运动功能丧失、疼痛、溃疡、尿路感染等病症，给患者带来极大的痛苦，也给家庭及社会带来了沉重的负担[1]。虽然对SCI的治疗已经取得很大的进步，但是到目前为止仍然没有十分满意的方法治疗SCI，其原因就是SCI后的病理变化过程非常复杂[2]，因此充分了解SCI后的病理过程的各个方面对SCI的治疗有着非常重要的作用。
随着深入的研究，SCI的病理过程被分为原发性损伤和继发性损伤两个阶段。原发性损伤指：创伤直接造成的损伤；而由原发性损伤引起的继发性损伤的损伤范围及严重程度远大于原发性损伤。继发性损伤的机理主要包括：兴奋性毒性，自由基，血管的破坏及炎症反应等[3-5]。其中炎症反应是SCI过程中最重要的病理过程，对SCI的预后至关重要，而血液来源的浸润的巨噬细胞及脊髓本身活化的小胶质细胞是其主要的参与者[6,7]。近期的研究报道，SCI后损伤区的各种信号微环境可使巨噬/小胶质细胞发生极化[8]。
所谓极化就是巨噬细胞处在不同的微环境中表现出不同的功能表型[8]。它们可以极化为M1和M2两种主要的细胞亚群，即经典活化巨噬细胞和替代活化巨噬细胞[9]。经典活化M1型巨噬细胞是指在LPS+IFN-γ作用下诱导产生的。替代活化M2型巨噬细胞可由IL-4诱导获得。M1型巨噬细胞典型的特征是高水平的氧化代谢产物（如超氧化物和一氧化氮）促炎症细胞因子（如IL-12, IL-1β, TNF-,IL-15, IL-18）[10,11]。这些物质会对神经元及胶质细胞产生细胞毒性作用[12]。而M2型巨噬细胞产生高水平的精氨酸酶1（arginase1），CD206，IL-10和TGF-β [13,14]，同时也会分泌一些神经营养因子（如睫状神经营养因子、胰岛素样生长因子、表皮生长因子、神经生长因子）[8,15]。这些物质可以发挥调节免疫反应，促进组织修复和功能重塑的作用。因此SCI后，巨噬/小胶质细胞既可以加剧SCI，也可以减轻SCI促进功能恢复。而SCI后不同阶段M1型巨噬细胞和M2型巨噬细胞的比例决定着SCI的转归[8]。
Programmed cell death（PD-1）是一个由288个氨基酸组成的I型跨膜蛋白，属于CD28家族。其氨基酸序列与CTLA-4的序列有23%的同源[16]。PD-1作为一个共抑制受体，其功能在T淋巴细胞中阐述的最为详尽。当它的配体PD-L与受体PD-1结合后，募集蛋白酪氨酸磷酸酶SHP-2或SHP-1/SHP-2与其胞内段的ITIM和ITSM结合，从而抑制T淋巴细胞增殖和细胞因子的产生[17,18]。PD-1信号通路与巨噬细胞的活动密切相关，这已被最近的报道所提示[19]。Said等报道HIV感染后单核细胞PD-1的表达明显上调[20]；Ma等报道丙型肝炎病毒感染后，PD-1可以通过抑制巨噬细胞STAT1（signal transducer and activator of transcription1）的磷酸化来负性调控IL-12的分泌[21]。但是PD-1途径是否参与调控巨噬/小胶质细胞的极化，如何来调控，尤其是SCI后PD-1途径发挥什么样的功能有待于进一步的研究。
在本课题中，我们引进了C57BL/6背景的PD-1敲除小鼠，体外分别培养野生型和PD-1敲除两种小鼠的巨噬细胞和小胶质细胞，来观察PD-1在巨噬/小胶质细胞极化过程中的作用，并初步探讨其作用机制。
本课题所取得的结果分述如下：
1.首先，在体外培养了来源于野生小鼠和PD-1敲除小鼠的巨噬细胞和小胶质细胞，并给予LPS+IFN-γ和IL-4分别诱导为M1和M2表型，我们发现PD-1参与调节了巨噬/小胶质细胞的极化，PD-1敲除的巨噬/小胶质细胞更容易被诱导成M1型。
2. PD-1敲除的巨噬/小胶质细胞会分泌更多的M1型特征的炎症因子（IL-1、TNF-、IL-12、IFN-γ等），同时分泌较少的M2型特征的炎症因子（IL-10，IL-4等）。
3. STAT1和STAT6在巨噬/小胶质细胞存在有相互拮抗的现象，而PD-1主要通过调节JAK-STAT （janus kinase-signal transducer and activator oftranscription）通路而发挥其调节巨噬/小胶质细胞极化的作用。
4.我们发现巨噬细胞和小胶质细胞吞噬葡聚糖珠的能力上面有明显的不同。
5.最后我们在体内检测了SCI后PD-1的表达时程，并通过两种小鼠的比较，发现PD-1在SCI后起到的作用。
综上所述，PD-1通路在调控巨噬/小胶质细胞极化中发挥着重要的作用。缺失PD-1使巨噬/小胶质细胞以削弱M2型为代价偏向于被极化为M1型。巨噬细胞和小胶质细胞在吞噬葡聚糖珠子的能力上有巨大差异。在体内，SCI后PD-1的缺失使炎症加剧，功能恢复减慢。所有这些为SCI后调控巨噬/小胶质细胞的极化提供了新的手段，并为治疗SCI提供了新的思路。
About2.5million people live with spinal cord injury (SCI), with more than130000new cases reported annually [1]. SCI often cause paralysis with complications of pain,ulcer and urethra infection, which result in enormous suffering and burden to the familiesand society [1]. Although great progresses have made in treatment after SCI, there is nonesatisfactory therapy till now. The reason lies in the fact that the very complicatedpathological changes after SCI [2]. So well study and understand every aspect of thepathology after SCI has become the main tasks for neuroscience scientists.
With more and more study in this area, the pathological sequelae after SCI aredivided into two phases: primary injury and secondary injury. The primary injury meansthe direct damage caused by the trauma. Caused by the primary injury, the secondaryinjury leads to more seriouse extent than the primary injury. Several interrelated processes are thought to contribute to the secondary injury after SCI, including excitotoxity, freeradical, vascular broken and inflammatory responses et al [3-5]. In which, inflammatoryresponses plays the most important role and determines the recovery consequences. Andthe main inflammatory cells are macrophages/microglia the main inflammatory cells aremacrophages/microglia [6,7]. It is already known that macrophages/microglia can bepolarized into M1or M2based on signals in the lesion microenvironment [8].
Polarizaion means macrophages retain different functional phenotypes in differentmicroenvironments [8]. Macrophages can be mainly polarized into two phenotypes:“classic activated” M1phenotype macrophages and “alternative activated” M2phenotypemacrophages. in vitro, Lipopolysaccharide (LPS) and interferon-gamma (IFN-r) inducemacrophages/microglia into “classically activated”M1phenotype and interleukin-4(IL-4)or IL-13induces the cells into “alternatively activated” M2phenotype [9]. The phenotypethat defines M1macrophages/microglia is characterized by increased oxidativemetabolites (such as inducible nitric oxide synthase (iNOS) and nitric oxide synthase2(NOS2)) and high levels of pro-inflammatory cytokines (e.g., IL-12, IL-1β, TNF-, IL-15,IL-18)[10,11], which is cytotoxic to neurons and glia cells [12]. Conversely, in thepresence of IL-4, macrophages/microglia will be polarized into M2phenotype andproduce high levels of Arginase1(Arg1), CD206, IL-10and TGF-β [13,14], and alsosecret kinds of neurotrophic factors (e.g., CNTF, IGF, EGF, NGF), which suppressinflammatory responses and facilitate wound healing [8,15]. In SCI, formacrophages/microglia, to facilitate or inhibit the recovery is determined by the ratio ofM1versus M2during pathological processes [8].
Programmed cell death1(PD-1) is a288amino acid type I transmembrane proteinwhich belongs to the CD28superfamily and shares23%amino acid sequence homologywith cytotoxic T-lymphocyte-associated antigen4(CTLA-4)[16]. As a co-inhibitoryreceptor, it has been well studied in T lymphocyte. Ligation of PD-1with its ligandPD-L1could recruit SHP-2or SHP-1/SHP-2to combine with its cytoplasmic domainimmunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM), and then inhibit proliferation and cytokineproduction of T lymphocyte [17]. A relationship between PD-1singnaling pathway andmacrophage activation has been suggested by several studies [19]. The upregulation ofPD-1has been reported in monocytes after HIV infection [20]. PD-1has been proved tonegatively regulate IL-12production by limiting STAT1(signal transducer and activatorof transcription1) phosphorylation in monocytes/macrophages during chronic hepatitis Cvirus infection [21]. While more studies need to be done to explore the roles of PD-1signaling pathway in the polarization of macrophages/microglia, especially its functionduring the process after SCI.
In this study, we have introduced PD-1knock out mice based on C57BL/6background mice. Macrophages and microglia were cultured from these two kinds ofmice. The roles and mechanisms of PD-1were detected in the polarization ofmacrophages/microglia in vitro.
The results we have obtained are as follows:
1. First, macrophages and microglia were cultured from C57BL/6(WT) mice andPD-1KO mice. Then LPS+IFN-γ and IL-4were given toinducedmacrophages/microglia into M1and M2phenotypes respectively. Wefound PD-1paticipated in the regulation of macrophages/microglia polarizationand PD-1KO macrophages/microglia were prone to be polarized into M1phenotype.
2. PD-1KO macrophages/microglia secreted more pro-inflammatory factors (IL-1,TNF-, IL-12, IFN-γ, et al) which were the characteristic of M1phenotype. Atthe same time secreted less anti-inflammatory fators (IL-10, IL-4, et al) whichwere the characteristic of M2phenotype
3. STAT1and STAT6were reciprocal antagonism in macrophages/microglia, andone of the mechanisms that PD-1regulated macrophages/microglia polarizationis through the regulation of janus kinase-STAT (JAK-STAT) pathway.
4. We found there were widely differences in phagocytosis lates beads between bone marrow derived macrophages and microglia.
5. In vivo, we detected the expression of PD-1and PD-L1at each time point afterSCI, and we found the roles of PD-1played through the comparation WT andPD-1KO mice after SCI.
In summary, PD-1signaling pathway plays important roles in regulation ofmacrophages/microglia polarization, and compromised PD-1signaling pathway,macrophages/microglia are prone to be polarized into M1phenotype in the expense of M2phenotype. There is wide difference between macrophages and microglia in thephagocytosis of latex beads. In vivo, PD-1deficient mice exacerbate inflammatoryresponses and retard functional recovery after SCI compared with WT mice. These resultsprovide new insights into the modulation mechanisms of macrophages/microgliapolarization and shed light on new therapies for SCI through the modulation ofmacrophages/microglia polarization through the PD-1signaling.
随着深入的研究，SCI的病理过程被分为原发性损伤和继发性损伤两个阶段。原发性损伤指：创伤直接造成的损伤；而由原发性损伤引起的继发性损伤的损伤范围及严重程度远大于原发性损伤。继发性损伤的机理主要包括：兴奋性毒性，自由基，血管的破坏及炎症反应等[3-5]。其中炎症反应是SCI过程中最重要的病理过程，对SCI的预后至关重要，而血液来源的浸润的巨噬细胞及脊髓本身活化的小胶质细胞是其主要的参与者[6,7]。近期的研究报道，SCI后损伤区的各种信号微环境可使巨噬/小胶质细胞发生极化[8]。
所谓极化就是巨噬细胞处在不同的微环境中表现出不同的功能表型[8]。它们可以极化为M1和M2两种主要的细胞亚群，即经典活化巨噬细胞和替代活化巨噬细胞[9]。经典活化M1型巨噬细胞是指在LPS+IFN-γ作用下诱导产生的。替代活化M2型巨噬细胞可由IL-4诱导获得。M1型巨噬细胞典型的特征是高水平的氧化代谢产物（如超氧化物和一氧化氮）促炎症细胞因子（如IL-12, IL-1β, TNF-,IL-15, IL-18）[10,11]。这些物质会对神经元及胶质细胞产生细胞毒性作用[12]。而M2型巨噬细胞产生高水平的精氨酸酶1（arginase1），CD206，IL-10和TGF-β [13,14]，同时也会分泌一些神经营养因子（如睫状神经营养因子、胰岛素样生长因子、表皮生长因子、神经生长因子）[8,15]。这些物质可以发挥调节免疫反应，促进组织修复和功能重塑的作用。因此SCI后，巨噬/小胶质细胞既可以加剧SCI，也可以减轻SCI促进功能恢复。而SCI后不同阶段M1型巨噬细胞和M2型巨噬细胞的比例决定着SCI的转归[8]。
Programmed cell death（PD-1）是一个由288个氨基酸组成的I型跨膜蛋白，属于CD28家族。其氨基酸序列与CTLA-4的序列有23%的同源[16]。PD-1作为一个共抑制受体，其功能在T淋巴细胞中阐述的最为详尽。当它的配体PD-L与受体PD-1结合后，募集蛋白酪氨酸磷酸酶SHP-2或SHP-1/SHP-2与其胞内段的ITIM和ITSM结合，从而抑制T淋巴细胞增殖和细胞因子的产生[17,18]。PD-1信号通路与巨噬细胞的活动密切相关，这已被最近的报道所提示[19]。Said等报道HIV感染后单核细胞PD-1的表达明显上调[20]；Ma等报道丙型肝炎病毒感染后，PD-1可以通过抑制巨噬细胞STAT1（signal transducer and activator of transcription1）的磷酸化来负性调控IL-12的分泌[21]。但是PD-1途径是否参与调控巨噬/小胶质细胞的极化，如何来调控，尤其是SCI后PD-1途径发挥什么样的功能有待于进一步的研究。
在本课题中，我们引进了C57BL/6背景的PD-1敲除小鼠，体外分别培养野生型和PD-1敲除两种小鼠的巨噬细胞和小胶质细胞，来观察PD-1在巨噬/小胶质细胞极化过程中的作用，并初步探讨其作用机制。
本课题所取得的结果分述如下：
1.首先，在体外培养了来源于野生小鼠和PD-1敲除小鼠的巨噬细胞和小胶质细胞，并给予LPS+IFN-γ和IL-4分别诱导为M1和M2表型，我们发现PD-1参与调节了巨噬/小胶质细胞的极化，PD-1敲除的巨噬/小胶质细胞更容易被诱导成M1型。
2. PD-1敲除的巨噬/小胶质细胞会分泌更多的M1型特征的炎症因子（IL-1、TNF-、IL-12、IFN-γ等），同时分泌较少的M2型特征的炎症因子（IL-10，IL-4等）。
3. STAT1和STAT6在巨噬/小胶质细胞存在有相互拮抗的现象，而PD-1主要通过调节JAK-STAT （janus kinase-signal transducer and activator oftranscription）通路而发挥其调节巨噬/小胶质细胞极化的作用。
4.我们发现巨噬细胞和小胶质细胞吞噬葡聚糖珠的能力上面有明显的不同。
5.最后我们在体内检测了SCI后PD-1的表达时程，并通过两种小鼠的比较，发现PD-1在SCI后起到的作用。
综上所述，PD-1通路在调控巨噬/小胶质细胞极化中发挥着重要的作用。缺失PD-1使巨噬/小胶质细胞以削弱M2型为代价偏向于被极化为M1型。巨噬细胞和小胶质细胞在吞噬葡聚糖珠子的能力上有巨大差异。在体内，SCI后PD-1的缺失使炎症加剧，功能恢复减慢。所有这些为SCI后调控巨噬/小胶质细胞的极化提供了新的手段，并为治疗SCI提供了新的思路。
About2.5million people live with spinal cord injury (SCI), with more than130000new cases reported annually [1]. SCI often cause paralysis with complications of pain,ulcer and urethra infection, which result in enormous suffering and burden to the familiesand society [1]. Although great progresses have made in treatment after SCI, there is nonesatisfactory therapy till now. The reason lies in the fact that the very complicatedpathological changes after SCI [2]. So well study and understand every aspect of thepathology after SCI has become the main tasks for neuroscience scientists.
With more and more study in this area, the pathological sequelae after SCI aredivided into two phases: primary injury and secondary injury. The primary injury meansthe direct damage caused by the trauma. Caused by the primary injury, the secondaryinjury leads to more seriouse extent than the primary injury. Several interrelated processes are thought to contribute to the secondary injury after SCI, including excitotoxity, freeradical, vascular broken and inflammatory responses et al [3-5]. In which, inflammatoryresponses plays the most important role and determines the recovery consequences. Andthe main inflammatory cells are macrophages/microglia the main inflammatory cells aremacrophages/microglia [6,7]. It is already known that macrophages/microglia can bepolarized into M1or M2based on signals in the lesion microenvironment [8].
Polarizaion means macrophages retain different functional phenotypes in differentmicroenvironments [8]. Macrophages can be mainly polarized into two phenotypes:“classic activated” M1phenotype macrophages and “alternative activated” M2phenotypemacrophages. in vitro, Lipopolysaccharide (LPS) and interferon-gamma (IFN-r) inducemacrophages/microglia into “classically activated”M1phenotype and interleukin-4(IL-4)or IL-13induces the cells into “alternatively activated” M2phenotype [9]. The phenotypethat defines M1macrophages/microglia is characterized by increased oxidativemetabolites (such as inducible nitric oxide synthase (iNOS) and nitric oxide synthase2(NOS2)) and high levels of pro-inflammatory cytokines (e.g., IL-12, IL-1β, TNF-, IL-15,IL-18)[10,11], which is cytotoxic to neurons and glia cells [12]. Conversely, in thepresence of IL-4, macrophages/microglia will be polarized into M2phenotype andproduce high levels of Arginase1(Arg1), CD206, IL-10and TGF-β [13,14], and alsosecret kinds of neurotrophic factors (e.g., CNTF, IGF, EGF, NGF), which suppressinflammatory responses and facilitate wound healing [8,15]. In SCI, formacrophages/microglia, to facilitate or inhibit the recovery is determined by the ratio ofM1versus M2during pathological processes [8].
Programmed cell death1(PD-1) is a288amino acid type I transmembrane proteinwhich belongs to the CD28superfamily and shares23%amino acid sequence homologywith cytotoxic T-lymphocyte-associated antigen4(CTLA-4)[16]. As a co-inhibitoryreceptor, it has been well studied in T lymphocyte. Ligation of PD-1with its ligandPD-L1could recruit SHP-2or SHP-1/SHP-2to combine with its cytoplasmic domainimmunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM), and then inhibit proliferation and cytokineproduction of T lymphocyte [17]. A relationship between PD-1singnaling pathway andmacrophage activation has been suggested by several studies [19]. The upregulation ofPD-1has been reported in monocytes after HIV infection [20]. PD-1has been proved tonegatively regulate IL-12production by limiting STAT1(signal transducer and activatorof transcription1) phosphorylation in monocytes/macrophages during chronic hepatitis Cvirus infection [21]. While more studies need to be done to explore the roles of PD-1signaling pathway in the polarization of macrophages/microglia, especially its functionduring the process after SCI.
In this study, we have introduced PD-1knock out mice based on C57BL/6background mice. Macrophages and microglia were cultured from these two kinds ofmice. The roles and mechanisms of PD-1were detected in the polarization ofmacrophages/microglia in vitro.
The results we have obtained are as follows:
1. First, macrophages and microglia were cultured from C57BL/6(WT) mice andPD-1KO mice. Then LPS+IFN-γ and IL-4were given toinducedmacrophages/microglia into M1and M2phenotypes respectively. Wefound PD-1paticipated in the regulation of macrophages/microglia polarizationand PD-1KO macrophages/microglia were prone to be polarized into M1phenotype.
2. PD-1KO macrophages/microglia secreted more pro-inflammatory factors (IL-1,TNF-, IL-12, IFN-γ, et al) which were the characteristic of M1phenotype. Atthe same time secreted less anti-inflammatory fators (IL-10, IL-4, et al) whichwere the characteristic of M2phenotype
3. STAT1and STAT6were reciprocal antagonism in macrophages/microglia, andone of the mechanisms that PD-1regulated macrophages/microglia polarizationis through the regulation of janus kinase-STAT (JAK-STAT) pathway.
4. We found there were widely differences in phagocytosis lates beads between bone marrow derived macrophages and microglia.
5. In vivo, we detected the expression of PD-1and PD-L1at each time point afterSCI, and we found the roles of PD-1played through the comparation WT andPD-1KO mice after SCI.
In summary, PD-1signaling pathway plays important roles in regulation ofmacrophages/microglia polarization, and compromised PD-1signaling pathway,macrophages/microglia are prone to be polarized into M1phenotype in the expense of M2phenotype. There is wide difference between macrophages and microglia in thephagocytosis of latex beads. In vivo, PD-1deficient mice exacerbate inflammatoryresponses and retard functional recovery after SCI compared with WT mice. These resultsprovide new insights into the modulation mechanisms of macrophages/microgliapolarization and shed light on new therapies for SCI through the modulation ofmacrophages/microglia polarization through the PD-1signaling.
引文
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