中华放射医学与防护杂志  2023, Vol. 43 Issue (10): 839-844   PDF    
辐射对巨噬细胞极化和功能的调节作用
李卫国 , 高刚 , 潘艳 , 阮健磊 , 刘建香     
中国疾病预防控制中心辐射防护与核安全医学所 辐射防护与核应急中国疾病预防控制中心重点实验室, 北京 100088
[摘要] 巨噬细胞是存在于所有组织中的调节性细胞, 它们对辐射刺激的反应机制复杂, 既有共同的应对感染、损伤的变化过程, 也有自己独特的极化转变方式。辐射相关的极化转变决定了巨噬细胞的功能类型。巨噬细胞受到不同的照射后, 受到不同细胞因子的调节, 涉及多个信号通路, 极化程度也有所不同。本文综述辐射对巨噬细胞极化和功能的调节作用, 以期对免疫基础研究和临床放射治疗提供参考。
[关键词] 巨噬细胞    极化    辐射    信号通路    
A review of regulatory effects of radiation on the polarization and functions of macrophages
Li Weiguo , Gao Gang , Pan Yan , Ruan Jianlei , Liu Jianxiang     
Key Laboratory of Radiological Protection and Nuclear Emergency, China CDC, National Institute for Radiological Protection, Chinese Center for Disease Control and Protection, Beijing 100088, China
[Abstract] Macrophages, as regulatory cells existing in all tissues, exhibit complex responses to radiation stimulation, including both common processes in response to infection and injury and unique polarization transformation. Radiation-related polarization determines the functional types of macrophages. After being exposed to different irradiations, macrophages are regulated by different cytokines, involving multiple signaling pathways. This leads to differential degrees of polarization. The review summarized the regulatory effects of radiation on the polarization and functions of macrophages in order to provide basis for theoretical research on immunity and clinical radiotherapy.
[Key words] Macrophage    Polarization    Radiation    Signaling pathway    

巨噬细胞存在于成年哺乳动物的所有组织中,被认为是驻留组织的组成部分,在局部微环境的驱动下,显示出明显的的形态和功能的多样性[1-4]。在对巨噬细胞的功能研究中,逐渐形成了比较实用又被认可的一种巨噬细胞分类方法,即在非病原体刺激条件下衍生的M1和M2型巨噬细胞[5-7]。M1型由γ干扰素(IFN-γ)和激活的Toll样受体刺激产生,而M2型由白介素4(IL-4)和IL-13刺激产生。事实上,这种二分类法也不能涵盖复杂的体内环境中的全部巨噬细胞的特征,在具体环境中,许多细胞因子、炎症介质、趋化因子等相互作用共同决定巨噬细胞的发育分化状态。巨噬细胞在机体生物学的几乎每个方面,包括从发育、稳态和修复,到对病原体的免疫反应都发挥作用。面对外部的挑战,常驻巨噬细胞会及时做出反应来调节组织的动态平衡。

辐射作为一种破坏稳态的外部施加因素,对维护稳态的巨噬细胞功能改变具有明显的刺激作用。本文将着重描述辐射对巨噬细胞极化、修复重塑、功能促发的作用及具体机制,以期对相关基础研究和肿瘤放疗提供参考。

一、巨噬细胞在生理和病理情况下的作用

1. 巨噬细胞的起源:从起源上讲,巨噬细胞被认为是由巨噬细胞祖细胞严格按照分化时间序列产生的[8]。大多数成年小鼠长期驻留组织的巨噬细胞在胚胎发育过程中来源于卵黄囊[9],它们具有自我更新能力并且独立于单核细胞分化的细胞。出生后骨髓发挥造血作用,向外周血液供应单核细胞,在趋化因子等引导下进入各个组织,分化为功能巨噬细胞。成年后,胚胎和成人来源的巨噬细胞在许多器官中共存[10-12]。无论其来源如何,巨噬细胞发育和分化受到众多细胞因子的调节[13],如巨噬细胞集落刺激因子1受体(CSF1R)、粒细胞-巨噬细胞集落刺激因子(GM-CSF)、IL-3、血管内皮生长因子A(VEGFA),转录因子SFPI1(PU.1)[14]、Mafb(v-Maf)[15]、Fos、Mitf,这些调节因子对保持巨噬细胞的数量和特定功能至关重要。还有许多调节因子有助于细分巨噬细胞亚群,如Mitf(micropthalmia)家族成员、Tcf3、Cebpa、Bach1、Creg1和亚群特有的转录因子,包括Gata6和Spic[16]

2. 巨噬细胞在生理状态下的功能及分子反应:巨噬细胞的固有特性,包括从细胞内到细胞外的感知、机体整体适应、吞噬、降解,巨噬细胞似乎特别专注于体内平衡和组织完整性。特化的组织驻留巨噬细胞功能各不相同,肠道中不同类型的巨噬细胞共同作用以维持对正常肠道菌群和口服抗原的耐受以及肠道完整性[17],小胶质细胞、破骨细胞、肺泡巨噬细胞,脾脏和间质结缔组织中的组织细胞、肝枯否细胞[12, 18]、眼睛、睾丸中的巨噬细胞,它们在血管延伸、组织重塑和体内平衡中起核心作用[19-20]

巨噬细胞具有灵活的可塑性,对每个特定组织中遇到的微环境刺激或信号产生不同功能反应。局部细胞因子可以引导巨噬细胞由一种表型转换为另一种表型[6]。学者们大多接受两种极端的极化分类:M1型和M2型(表 1)。M1巨噬细胞活化导致促炎细胞因子的诱导[21-23],从而提供一种有效的病原体杀灭机制。而M2巨噬细胞通过将基因表达转换产生抗炎分子。

表 1 小鼠中M1和M2巨噬细胞的表型和功能 Table 1 Phenotypes and functions of M1 and M2 macrophages in mice

3. 巨噬细胞在病理状态下的功能及表型:在不同的病理环境下,巨噬细胞会根据需要进行功能及表型转化,它们的极化状态有时决定了疾病的进展或消退[24]。M1巨噬细胞对感染细胞具有强大的细胞毒功能,并介导对感染的抵抗[25-26]。微生物刺激,如脂多糖(LPS)诱导M1表型极化,这是宿主对细胞内病原体(如细菌)反应的关键效应,并支持强大的活性氧(ROS)的产生。相反,IL-4和IL-13诱导交替激活的M2表型极化,抑制Th1反应[27-29],从而限制炎症。

肿瘤相关巨噬细胞通常表现出M2样表型,是肿瘤微环境的主要浸润性白细胞,是炎症与癌症之间联系的关键参与者[30],在肿瘤中产生高水平的IL-10和TGF-β[29],从而阻断T细胞增殖。它们没有细胞毒活性[7],同时为癌细胞产生生长因子,溶解细胞外基质促血管生长[7]和肿瘤溢出[31-32],并具有免疫抑制活性[30, 33]。如果将肿瘤巨噬细胞的表型转向M1,在理论上可抑制肿瘤的生长和扩散[34-35]

另外,巨噬细胞在伤口愈合的不同阶段[19, 36]、过敏、肥胖、糖尿病、动脉粥样硬化等疾病中承担重要角色[29, 37-39]

二、辐射对巨噬细胞极化的调节作用

细胞对辐射的最初反应涉及从受照射细胞中释放被称为损伤相关分子模式(DAMP)的先天危险信号,以响应辐射诱导的损伤[40]。这种过程的部分特征是释放高迁移率族蛋白盒1(HMGB1)、钙网蛋白(CRT)的表达、ATP释放到细胞外空间、热休克蛋白(HSP)的产生[41]和双链DNA泄漏到细胞质中[42]。巨噬细胞可以通过表达众多因子来感知这些先天性炎症分子[43],如与HMGB1作用的TLR4、与ATP作用的NOD样蛋白受体3(NLRP3)、钙网蛋白的低密度脂蛋白受体相关蛋白(LRP)和环GMP-AMP(cGAMP)合酶(cGAS)、DNA干扰素基因(STING)适配器刺激物。这些受体的下游信号传导集中在NF-κB通路,导致级联炎症反应。这种信号大部分发生在驻组织的巨噬细胞、树突细胞,辐射照射后对组织基质的分析显示,M2巨噬细胞数量增加,它们对辐射介导的死亡具有抵抗力,并增强了募集功能[7, 44-46]

辐射诱导产生的M1与M2巨噬细胞的平衡可能取决于辐射剂量,即单位质量介质收到的辐射能量(Gy=J/kg)。单纯照射即可诱导巨噬细胞功能的改变,低剂量(单剂量<1.0 Gy) 照射主要诱导巨噬细胞的抗炎激活,而高剂量(≥1 Gy)照射更容易增强巨噬细胞的促炎特性[47-49]。如0.5 Gy的X射线对LPS活化的BALB/c腹腔巨噬细胞进行离体照射,导致促炎细胞因子IL-1β的分泌减少,而抗炎细胞因子TGF-β的分泌增加,表明低剂量照射促进了抗炎性巨噬细胞表型[50]。相反,1~5 Gy的照射增强了IFN-γ和LPS刺激的J774.1和RAW264.7巨噬细胞中iNOS和NO的产生。然而,也有报道显示,全身低剂量(0.04 Gy,照射5次)γ射线照射增强了C57BL/6小鼠的巨噬细胞吞噬作用和NO生成,同时增加了CD8+T细胞反应,表明低剂量照射在这种情况下具有免疫刺激作用。

人们也对辐射影响具体器官中巨噬细胞极化进行了大量研究,如关于辐射对肺部M1和M2细胞的调节过程的研究较为成熟。巨噬细胞极化和发挥功能受Th1/Th2的协调,肺部受照细胞DNA的损伤和活性氧继发损伤,招募的炎性细胞刺激Th1分泌IFN-γ等,促进经典的活化巨噬细胞(M1)表达一氧化氮合酶等效应分子,促成放射性肺炎的发展[51]。损伤进展中晚期,Th2活性增强,生成IL-4和IL-13可以促进旁路活化巨噬细胞(M2)中精氨酸酶等效应分子生成[52],并激活肌成纤维细胞,促进肺纤维化[8]。在炎症消退阶段,M2细胞在抑制免疫反应、恢复组织稳态中起主要作用,如放射治疗诱导HIF-1α的转录,导致CXCL-12、CCL-2、CSF1和VEGF的表达增加,从而支持血管生成、募集巨噬细胞并促进其免疫抑制功能,还诱导肿瘤相关巨噬细胞和肿瘤细胞中PD-L1的表达,从而抑制抗肿瘤的炎症反应[53]

三、各种调节因子对受照后巨噬细胞极化的调节作用

从功能适应上,M1巨噬细胞用于急性感染、损伤发生时的快速防御启动,除了通过激活烟酰胺腺嘌呤二核苷酸磷酸(NADPH)氧化酶系统和随后生成的活性氧(ROS)参与感染期间病原体的清除,还有抗原提呈、清除凋亡等功能。炎症后期M2巨噬细胞抗炎功能驱动的调节机制逐渐启动并占据主要地位[27, 29, 54-57],反向调节重新形成新的平衡。调节通路上涉及的分子类型不同,M1巨噬细胞通常由Th1细胞因子(如IFN-γ和TNF-α)或通过细菌脂多糖(LPS)识别诱导。具有抗炎作用的M2巨噬细胞被Th2细胞因子IL-4、IL-13、IL-10极化[58]。还有很多研究证实白介素广泛参与放射损伤细胞的转归过程。一项研究发现,HPV16+癌细胞产生的IL-6特别有利于辐射诱导的巨噬细胞极化为免疫刺激M1型,这与建立有效的抗肿瘤免疫有关。其他白介素如IL-33、IL-21也是驱动M2极化的Th2相关细胞因子。根据接受的刺激物不同,M2巨噬细胞可以进一步分为M2a、M2b、M2c和M2d 4个子集[59],它们的表型和调节因子有所差异。

辐射激活巨噬细胞产生NO的机制并不明确,但这种现象对于防止辐射损伤和增加肿瘤放射治疗的意义重大。早年的照射实验证明辐射可协同增加TNF-α、LPS、IFN-γ,刺激巨噬细胞增加NO产量[56, 60]。后来人们逐渐认识到巨噬细胞受照后iNOs表达升高,巨噬细胞主要表现出M1的特征,受照数天后巨噬细胞分泌IL-10和TGF-β,诱导精氨酸酶(arginase)抑制NO的产生,相关巨噬细胞表现为M2型,可见NO的产生和受照局部巨噬细胞所处的生态环境有关并随之变化。

p53缺失小鼠的实验表明,p53调节的凋亡程序可能是刺激巨噬细胞活化的起始环节,清除辐射导致的凋亡细胞后仍可产生持久的巨噬细胞激活和炎症反应。受照后巨噬细胞出现了广泛的53相关基因修饰,表明巨噬细胞对辐射损伤的复杂反应是基因修饰的过程。巨噬细胞对辐射诱导的凋亡的短期反应及其基因修饰可能是后期效应延续的重要决定因素[61]

CSF1R在巨噬细胞分化中很重要,在放射治疗中也发挥重要的调节作用,在鼠前列腺癌模型中,辐射通过DNA损伤诱导的Abelson鼠白血病病毒癌基因同源物ABL1的核易位,促进肿瘤细胞中CSF-1的表达,增加的CSF-1诱导肿瘤相关巨噬细胞和髓源性抑制细胞(MDSCs)的募集,这个过程可以通过选择性CSF-1R抑制剂实验进行消除。因此,辐射和CSF-1R抑制剂的联合治疗显著提高了抗肿瘤功效[62]

四、辐射引起巨噬细胞极化过程中涉及的主要信号通路

Notch通路作为一种高度保守的调节细胞分化和发育的信号通路,广泛参与各种疾病的发生和发展。Notch信号在M1巨噬细胞中的信号比M2巨噬细胞激活更强[63]。通过从小鼠体内敲除Notch信号通路的关键转录因子RBP-J,Notch信号通路被阻断,巨噬细胞不可逆地转化为M2表型,从而促进肿瘤的增殖、迁移、侵袭和免疫逃逸。据报道,RBP-J通过经典的Notch信号通路激活TLR4,诱导MNK1-eIF4E-IRAK2磷酸化,引起IRF8的翻译高表达,从而诱导M1标志物的表达和促进M1巨噬细胞的炎症反应[64]。因此,Notch信号通路是参与巨噬细胞极化调控的主要通路。肿瘤放射治疗实验发现,γ-分泌酶抑制剂GSI(Notch通路抑制剂)和放射治疗相结合的抗肿瘤效果取决于治疗计划,照射后给予γ-分泌酶抑制剂在体外和体内对肺癌的生长抑制作用最大。该组合通过调节MAPK和Bcl-2家族蛋白诱导肺癌细胞系的凋亡[65]。也有的文献细化了不同Notch受体的作用,证实辐射和Notch4受体通过降低肿瘤血流抑制肿瘤[66]

NF-κB通路是另一个重要的辐射损伤信号传导通路。大剂量辐射照射达到10 Gy(2 Gy/d)后,尽管巨噬细胞DNA损伤严重,但细胞仍保持活力,代谢增高,细胞通过激活NF-κB,减弱抗炎作用,增加吞噬作用。NF-κB家族的5个亚基RelA、RelB、cRel、p52/p100和p50/p105对辐射的反应有所不同。RelB的改变表明电离辐射上调巨噬细胞NF-κB,提示其核易位和随后的激活。MAPKp38也是炎症因子转录的关键调控分子,之前的实验表明,低/中等剂量的X射线照射影响p38的表达,通过MAPK通路减轻炎症[67]。另外,TLR是辐射调节巨噬细胞极性的重要受体,有实验表明在0.05~4 Gy的X射线受照范围内,IL-12和IL-18的分泌量呈剂量依赖性增加,二者可能通过激活巨噬细胞中的Toll信号通路来调节[68]

五、肿瘤相关巨噬细胞M2样表型在放射治疗中的前景

从受照肿瘤的微环境中分离的肿瘤相关巨噬细胞(TAMs)可促进肿瘤生长[69],并增强肿瘤抗辐射的能力,这种抗性可能部分归因于照射后巨噬细胞的“促肿瘤”M2样表型,而且,消除或抑制TAMs的M2样表型与放射治疗联合使用的策略已显示出增强抗肿瘤的功效[70-72]。如单纯放疗对胰腺胆管腺癌细胞生长抑制作用不明显,若同时抑制CCL2的功能则可明显增强辐射抑制腺癌生长,相关巨噬细胞在受照数天后虽表现为M2型,却无法恢复其促侵袭和促血管生成特征[73],这对抑制肿瘤具有重要的提示意义。最近对常驻组织巨噬细胞的转录分析证明,microRNAs对巨噬细胞极化有重要的调节作用。M1巨噬细胞极化需要miRNA-125[74]、miRNA-146、miRNA-155、miRNA-let-7a/f和miRNA-378,而M2极化需要miRNA-let-7c/e、miRNA-9、miRNA-21、miRNA-146、miRNA-147、miRNA-187和miRNA-223。开发以巨噬细胞特异性方式递送miRNA的载体可能调节TAMs的表型,从而大大增加放射治疗的效果,为肿瘤治疗开辟一个新的方向。

六、总结

由于巨噬细胞具有组织异质性,不同部位、不同疾病中巨噬细胞对辐射的反应差别较大,这应该和组织的微环境有很大关系。巨噬细胞极化的分类是为了更好地掌握细胞反应规律而总结,这种分类和相关研究对于巨噬细胞对辐射的反应研究和临床放射治疗具有重要的指导意义;但M1和M2有时分界并不明显,甚至二者可再细分出多个亚型或组织特异型,未来随着研究的深入,细胞转变的标志物会更加具体多样。

利益冲突  所有作者声明不存在利益冲突

作者贡献声明  李卫国负责查阅文献、撰写稿件;高刚、潘艳、阮健磊负责论文构思、指导文献检索;刘建香负责确定综述主题、修改论文

参考文献
[1]
Hussell T, Bell TJ. Alveolar macrophages: plasticity in a tissue-specific context[J]. Nat Rev Immunol, 2014, 14(2): 81-93. DOI:10.1038/nri3600
[2]
Epelman S, Lavine KJ, Randolph GJ. Origin and functions of tissue macrophages[J]. Immunity, 2014, 41(1): 21-35. DOI:10.1016/j.immuni.2014.06.013
[3]
Okabe Y, Medzhitov R. Tissue biology perspective on macrophages[J]. Nat Immunol, 2016, 17(1): 9-17. DOI:10.1038/ni.3320
[4]
Ginhoux F, Guilliams M. Tissue-resident macrophage ontogeny and homeostasis[J]. Immunity, 2016, 44(3): 439-449. DOI:10.1016/j.immuni.2016.02.024
[5]
Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions[J]. Immunity, 2010, 32(5): 593-604. DOI:10.1016/j.immuni.2010.05.007
[6]
Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas[J]. J Clin Invest, 2012, 122(3): 787-795. DOI:10.1172/JCI59643
[7]
Shi X, Shiao SL. The role of macrophage phenotype in regulating the response to radiation therapy[J]. Transl Res, 2018, 191: 64-80. DOI:10.1016/j.trsl.2017.11.002
[8]
Gordon S. Alternative activation of macrophages[J]. Nat Rev Immunol, 2003, 3(1): 23-35. DOI:10.1038/nri978
[9]
Hashimoto D, Chow A, Noizat C, et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes[J]. Immunity, 2013, 38(4): 792-804. DOI:10.1016/j.immuni.2013.04.004
[10]
Galli SJ, Borregaard N, Wynn TA. Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils[J]. Nat Immunol, 2011, 12(11): 1035-1044. DOI:10.1038/ni.2109
[11]
Stefater JA 3rd, Ren S, Lang RA, et al. Metchnikoff's policemen: macrophages in development, homeostasis and regeneration[J]. Trends Mol Med, 2011, 17(12): 743-752. DOI:10.1016/j.molmed.2011.07.009
[12]
Varol C, Mildner A, Jung S. Macrophages: development and tissue specialization[J]. Annu Rev Immunol, 2015, 33: 643-675. DOI:10.1146/annurev-immunol-032414-112220
[13]
Hume DA. Plenary perspective: the complexity of constitutive and inducible gene expression in mononuclear phagocytes[J]. J Leukoc Biol, 2012, 92(3): 433-444. DOI:10.1189/jlb.0312166
[14]
Schulz C, Gomez Perdiguero E, Chorro L, et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells[J]. Science, 2012, 336(6077): 86-90. DOI:10.1126/science.1219179
[15]
Geissmann F, Manz MG, Jung S, et al. Development of monocytes, macrophages, and dendritic cells[J]. Science, 2010, 327(5966): 656-661. DOI:10.1126/science.1178331
[16]
Gautier EL, Shay T, Miller J, et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages[J]. Nat Immunol, 2012, 13(11): 1118-1128. DOI:10.1038/ni.2419
[17]
Pull SL, Doherty JM, Mills JC, et al. Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury[J]. Proc Natl Acad Sci USA, 2005, 102(1): 99-104. DOI:10.1073/pnas.0405979102
[18]
Davies LC, Jenkins SJ, Allen JE, et al. Tissue-resident macrophages[J]. Nat Immunol, 2013, 14(10): 986-995. DOI:10.1038/ni.2705
[19]
Das A, Sinha M, Datta S, et al. Monocyte and macrophage plasticity in tissue repair and regeneration[J]. Am J Pathol, 2015, 185(10): 2596-2606. DOI:10.1016/j.ajpath.2015.06.001
[20]
Gordy C, Pua H, Sempowski GD, et al. Regulation of steady-state neutrophil homeostasis by macrophages[J]. Blood, 2011, 117(2): 618-629. DOI:10.1182/blood-2010-01-265959
[21]
Porta C, Riboldi E, Ippolito A, et al. Molecular and epigenetic basis of macrophage polarized activation[J]. Semin Immunol, 2015, 27(4): 237-248. DOI:10.1016/j.smim.2015.10.003
[22]
Schultze JL, Schmidt SV. Molecular features of macrophage activation[J]. Semin Immunol, 2015, 27(6): 416-423. DOI:10.1016/j.smim.2016.03.009
[23]
Schultze JL, Freeman T, Hume DA, et al. A transcriptional perspective on human macrophage biology[J]. Semin Immunol, 2015, 27(1): 44-50. DOI:10.1016/j.smim.2015.02.001
[24]
Divangahi M, King IL, Pernet E. Alveolar macrophages and type Ⅰ IFN in airway homeostasis and immunity[J]. Trends Immunol, 2015, 36(5): 307-314. DOI:10.1016/j.it.2015.03.005
[25]
Patel U, Rajasingh S, Samanta S, et al. Macrophage polarization in response to epigenetic modifiers during infection and inflammation[J]. Drug Discov Today, 2017, 22(1): 186-193. DOI:10.1016/j.drudis.2016.08.006
[26]
Weiss G, Schaible UE. Macrophage defense mechanisms against intracellular bacteria[J]. Immunol Rev, 2015, 264(1): 182-203. DOI:10.1111/imr.12266
[27]
Biswas SK, Chittezhath M, Shalova IN, et al. Macrophage polarization and plasticity in health and disease[J]. Immunol Res, 2012, 53(1-3): 11-24. DOI:10.1007/s12026-012-8291-9
[28]
Shapouri-Moghaddam A, Mohammadian S, Vazini H, et al. Macrophage plasticity, polarization, and function in health and disease[J]. J Cell Physiol, 2018, 233(9): 6425-6440. DOI:10.1002/jcp.26429
[29]
Sica A, Erreni M, Allavena P, et al. Macrophage polarization in pathology[J]. Cell Mol Life Sci, 2015, 72(21): 4111-4126. DOI:10.1007/s00018-015-1995-y
[30]
Belgiovine C, D'Incalci M, Allavena P, et al. Tumor-associated macrophages and anti-tumor therapies: complex links[J]. Cell Mol Life Sci, 2016, 73(13): 2411-2424. DOI:10.1007/s00018-016-2166-5
[31]
Vitale I, Manic G, Coussens LM, et al. Macrophages and metabolism in the tumor microenvironment[J]. Cell Metab, 2019, 30(1): 36-50. DOI:10.1016/j.cmet.2019.06.001
[32]
Pan Y, Yu Y, Wang X, et al. Tumor-associated macrophages in tumor immunity[J]. Front Immunol, 2020, 11: 583084. DOI:10.3389/fimmu.2020.583084
[33]
Ruffell B, Coussens LM. Macrophages and therapeutic resistance in cancer[J]. Cancer Cell, 2015, 27(4): 462-472. DOI:10.1016/j.ccell.2015.02.015
[34]
Pathria P, Louis TL, Varner JA. Targeting tumor-associated macrophages in cancer[J]. Trends Immunol, 2019, 40(4): 310-327. DOI:10.1016/j.it.2019.02.003
[35]
Feng M, Jiang W, Kim B, et al. Phagocytosis checkpoints as new targets for cancer immunotherapy[J]. Nat Rev Cancer, 2019, 19(10): 568-586. DOI:10.1038/s41568-019-0183-z
[36]
Mantovani A, Biswas SK, Galdiero MR, et al. Macrophage plasticity and polarization in tissue repair and remodelling[J]. J Pathol, 2013, 229(2): 176-185. DOI:10.1002/path.4133
[37]
Tabas I, Bornfeldt KE. Macrophage phenotype and function in different stages of atherosclerosis[J]. Circ Res, 2016, 118(4): 653-667. DOI:10.1161/CIRCRESAHA.115.306256
[38]
Lackey DE, Olefsky JM. Regulation of metabolism by the innate immune system[J]. Nat Rev Endocrinol, 2016, 12(1): 15-28. DOI:10.1038/nrendo.2015.189
[39]
Torres-Castro I, Arroyo-Camarena ÚD, Martínez-Reyes CP, et al. Human monocytes and macrophages undergo M1-type inflammatory polarization in response to high levels of glucose[J]. Immunol Lett, 2016, 176: 81-89. DOI:10.1016/j.imlet.2016.06.001
[40]
Ahmed MM, Guha C, Hodge JW, et al. Immunobiology of radiotherapy: new paradigms[J]. Radiat Res, 2014, 182(2): 123-125. DOI:10.1667/RR13849.1
[41]
Lumniczky K, Sáfrány G. The impact of radiation therapy on the antitumor immunity: local effects and systemic consequences[J]. Cancer Lett, 2015, 356(1): 114-125. DOI:10.1016/j.canlet.2013.08.024
[42]
Deng L, Liang H, Xu M, et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type Ⅰ interferon-dependent antitumor immunity in immunogenic tumors[J]. Immunity, 2014, 41(5): 843-852. DOI:10.1016/j.immuni.2014.10.019
[43]
Vanpouille-Box C, Alard A, Aryankalayil MJ, et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity[J]. Nat Commun, 2017, 8: 15618. DOI:10.1038/ncomms15618
[44]
Ahn GO, Tseng D, Liao CH, et al. Inhibition of Mac-1(CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment[J]. Proc Natl Acad Sci USA, 2010, 107(18): 8363-8368. DOI:10.1073/pnas.0911378107
[45]
Crittenden MR, Cottam B, Savage T, et al. Expression of NF-κB p50 in tumor stroma limits the control of tumors by radiation therapy[J]. PLoS One, 2012, 7(6): e39295. DOI:10.1371/journal.pone.0039295
[46]
DeNardo DG, Brennan DJ, Rexhepaj E, et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy[J]. Cancer Discov, 2011, 1(1): 54-67. DOI:10.1158/2159-8274.CD-10-0028
[47]
Teresa Pinto A, Laranjeiro Pinto M, Patrícia Cardoso A, et al. Ionizing radiation modulates human macrophages towards a pro-inflammatory phenotype preserving their pro-invasive and pro-angiogenic capacities[J]. Sci Rep, 2016, 6: 18765. DOI:10.1038/srep18765
[48]
Gough MJ, Young K, Crittenden M. The impact of the myeloid response to radiation therapy[J]. Clin Dev Immunol, 2013, 2013: 281958. DOI:10.1155/2013/281958
[49]
Wu Q, Allouch A, Martins I, et al. Macrophage biology plays a central role during ionizing radiation-elicited tumor response[J]. Biomed J, 2017, 40(4): 200-211. DOI:10.1016/j.bj.2017.06.003
[50]
Wunderlich R, Ernst A, Rödel F, et al. Low and moderate doses of ionizing radiation up to 2 Gy modulate transmigration and chemotaxis of activated macrophages, provoke an anti-inflammatory cytokine milieu, but do not impact upon viability and phagocytic function[J]. Clin Exp Immunol, 2015, 179(1): 50-61. DOI:10.1111/cei.12344
[51]
Yahyapour R, Shabeeb D, Cheki M, et al. Radiation protection and mitigation by natural antioxidants and flavonoids: implications to radiotherapy and radiation disasters[J]. Curr Mol Pharmacol, 2018, 11(4): 285-304. DOI:10.2174/1874467211666180619125653
[52]
Giuranno L, Ient J, De Ruysscher D, et al. Radiation-induced lung injury (RILI)[J]. Front Oncol, 2019, 9: 877. DOI:10.3389/fonc.2019.00877
[53]
Noman MZ, Desantis G, Janji B, et al. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation[J]. J Exp Med, 2014, 211(5): 781-790. DOI:10.1084/jem.20131916
[54]
Bashir S, Sharma Y, Elahi A, et al. Macrophage polarization: the link between inflammation and related diseases[J]. Inflamm Res, 2016, 65(1): 1-11. DOI:10.1007/s00011-015-0874-1
[55]
Cassetta L, Cassol E, Poli G. Macrophage polarization in health and disease[J]. Sci World J, 2011, 11: 2391-2402. DOI:10.1100/2011/213962
[56]
Locati M, Mantovani A, Sica A. Macrophage activation and polarization as an adaptive component of innate immunity[J]. Adv Immunol, 2013, 120: 163-184. DOI:10.1016/B978-0-12-417028-5.00006-5
[57]
Murray PJ. Macrophage Polarization[J]. Annu Rev Physiol, 2017, 79: 541-566. DOI:10.1146/annurev-physiol-022516-034339
[58]
Wang N, Liang H, Zen K. Molecular mechanisms that influence the macrophage M1-M2 polarization balance[J]. Front Immunol, 2014, 5: 614. DOI:10.3389/fimmu.2014.00614
[59]
Chistiakov DA, Bobryshev YV, Nikiforov NG, et al. Macrophage phenotypic plasticity in atherosclerosis: The associated features and the peculiarities of the expression of inflammatory genes[J]. Int J Cardiol, 2015, 184: 436-445. DOI:10.1016/j.ijcard.2015.03.055
[60]
Mckinney LC, Aquilla EM, Coffin D, et al. Ionizing radiation potentiates the induction of nitric oxide synthase by interferon-γ and/or lipopolysaccharide in murine macrophage cell lines: role of tumor necrosis factor-α[J]. Ann N Y Acad Sci, 2000, 899: 61-68. DOI:10.1111/j.1749-6632.2000.tb06176.x
[61]
Lorimore SA, Coates PJ, Scobie GE, et al. Inflammatory-type responses after exposure to ionizing radiation in vivo: a mechanism for radiation-induced bystander effects?[J]. Oncogene, 2001, 20(48): 7085-7095. DOI:10.1038/sj.onc.1204903
[62]
Xu J, Escamilla J, Mok S, et al. CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer[J]. Cancer Res, 2013, 73(9): 2782-2794. DOI:10.1158/0008-5472.CAN-12-3981
[63]
Di Bari M, Bevilacqua V, De Jaco A, et al. Mir-34a-5p mediates cross-talk between M2 muscarinic receptors and notch-1/EGFR pathways in U87MG glioblastoma cells: implication in cell proliferation[J]. Int J Mol Sci, 2018, 19(6): 1631. DOI:10.3390/ijms19061631
[64]
Xu H, Zhu J, Smith S, et al. Notch-RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization[J]. Nat Immunol, 2012, 13(7): 642-650. DOI:10.1038/ni.2304
[65]
Mizugaki H, Sakakibara-Konishi J, Ikezawa Y, et al. γ-Secretase inhibitor enhances antitumour effect of radiation in Notch-expressing lung cancer[J]. Br J Cancer, 2012, 106(12): 1953-1959. DOI:10.1038/bjc.2012.178
[66]
Liu SK, Bham SA, Fokas E, et al. Delta-like ligand 4-notch blockade and tumor radiation response[J]. J Natl Cancer Inst, 2011, 103(23): 1778-1798. DOI:10.1093/jnci/djr419
[67]
Carter AB, Monick MM, Hunninghake GW. Both Erk and p38 kinases are necessary for cytokine gene transcription[J]. Am J Respir Cell Mol Biol, 1999, 20(4): 751-758. DOI:10.1165/ajrcmb.20.4.3420
[68]
Shan YX, Jin SZ, Liu XD, et al. Ionizing radiation stimulates secretion of pro-inflammatory cytokines: dose-response relationship, mechanisms and implications[J]. Radiat Environ Biophys, 2007, 46(1): 21-29. DOI:10.1007/s00411-006-0076-x
[69]
Tsai CS, Chen FH, Wang CC, et al. Macrophages from irradiated tumors express higher levels of iNOS, arginase-Ⅰ and COX-2, and promote tumor growth[J]. Int J Radiat Oncol Biol Phys, 2007, 68(2): 499-507. DOI:10.1016/j.ijrobp.2007.01.041
[70]
De Palma M, Lewis CE. Macrophage regulation of tumor responses to anticancer therapies[J]. Cancer Cell, 2013, 23(3): 277-286. DOI:10.1016/j.ccr.2013.02.013
[71]
Hughes R, Qian BZ, Rowan C, et al. Perivascular M2 macrophages stimulate tumor relapse after chemotherapy[J]. Cancer Res, 2015, 75(17): 3479-3491. DOI:10.1158/0008-5472.CAN-14-3587
[72]
Brown JM, Thomas R, Nagpal S, et al. Macrophage exclusion after radiation therapy (MERT): A new and effective way to increase the therapeutic ratio of radiotherapy[J]. Radiother Oncol, 2020, 144: 159-164. DOI:10.1016/j.radonc.2019.11.020
[73]
Kalbasi A, Komar C, Tooker GM, et al. Tumor-derived CCL2 mediates resistance to radiotherapy in pancreatic ductal adenocarcinoma[J]. Clin Cancer Res, 2017, 23(1): 137-148. DOI:10.1158/1078-0432.CCR-16-0870
[74]
Li Q, He X, Yu Q, et al. The Notch signal mediates macrophage polarization by regulating miR-125a/miR-99b expression[J]. Artif Cells Nanomed Biotechnol, 2019, 47(1): 833-843. DOI:10.1080/21691401.2019.1576711