调控巨噬细胞极化影响创面愈合的因素及机制分析北大核心CSCD

巨噬细胞在创面愈合过程中可极化为经典途径激活的M1型(促炎)与交替途径激活的M2型(抗炎),通过多方面能力影响创面愈合。本文综述了调控创面巨噬细胞极化的多种理化机械因素:高血糖水平阻止创面巨噬细胞向M2型极化;组织滞留状态的铁促进创面巨噬细胞向M1型极化;循环状态的铁促进创面巨噬细胞向M2型极化;感染因素促进创面巨噬细胞向M1型极化;生理性电场促进创面巨噬细胞向M2型极化;基质硬度增强促进巨噬细胞向M1型极化等,并分析各因素影响创面愈合的机制,为创面修复提供更多思路。     

活性氧调控巨噬细胞极化的研究进展

巨噬细胞可以极化为两种表型:经典激活巨噬细胞(M1)和替代激活巨噬细胞(M2),前者分泌促炎细胞因子来促进炎性反应,而后者分泌炎性抑制因子抑制过量炎性反应、促进血管生成、组织修复和肿瘤生长等。作为重要的第二信使,活性氧(ROS)不仅导致促炎细胞因子的产生,而且促进肿瘤的发生和发展。在不同刺激条件下,ROS可调控巨噬细胞的极化过程,使其向不同表型转换,从而发挥不同作用。     

病原菌影响巨噬细胞极化的研究进展

巨噬细胞作为固有免疫系统中的重要一员,具有吞噬、抗原呈递、杀伤病原体等功能,在早期控制病原菌感染中发挥重要作用。病原菌可诱导巨噬细胞发生M1/M2型极化而参与机体对病原菌感染的免疫应答。病原菌运用不同的策略诱导巨噬细胞极化,对感染性疾病转归产生重要的影响。     

巨噬细胞的极化及功能调控

巨噬细胞在体内分布极广,具有高度可塑性,并在机体的发育及内环境的平衡中起到重要作用。应激条件下,巨噬细胞发生极化,极化后的巨噬细胞亚型可以细致调节及回应各种不同的刺激,对炎症反应或疾病的发展及组织器官的修复程度起着关键性的作用,具有重要的临床应用价值。我们在文中概述了巨噬细胞的极化分类,作用机制及不同环境下巨噬细胞的功能转换,为巨噬细胞极化研究提供理论基础。     

姜黄素对巨噬细胞的极化调节作用研究进展

巨噬细胞是创面愈合和组织修复过程的“总指挥”,对整个愈合过程具有不可替代的指导作用.巨噬细胞在不同微环境中可分别被诱导分化为M1型巨噬细胞和M2型巨噬细胞,前者在创面中能吞噬并清除外源性异物和坏死细胞,促进炎症反应的发生;后者在创面中通过释放各种细胞因子,调节创伤修复,抑制炎症反应的发生.不同极化状态的巨噬细胞在创伤愈合过程中发挥着不同的作用.姜黄素能够促进M0和(或)M1型巨噬细胞向M2型巨噬细胞极化.但至今姜黄素对巨噬细胞极化调节作用机制还尚不完全清楚.深入探讨姜黄素对巨噬细胞的调节机制及作用效应,将为创面愈合提供新的治疗策略和靶点.     

小鼠巨噬细胞功能极化可塑性的初步探讨

目的通过鉴定小鼠骨髓来源巨噬细胞(bone marrow-derived macrophages,BMDM)的功能表型,从而研究巨噬细胞功能极化的可塑性及其内在机制。方法采用流式细胞术检测体外诱导分化的小鼠骨髓来源巨噬细胞纯度;采用荧光定量PCR技术检测由RAW264.7极化的M1、M2巨噬细胞中M1、M2特定标记基因的表达来鉴定RAW264.7的功能状态;小鼠BMDM极化为M1、M2巨噬细胞时,荧光定量PCR技术检测M1、M2中特定标记基因TNF-α、IL-6、Arginase、Fizz-1 mRNA水平的表达,组蛋白去乙酰化酶抑制剂Trichostatin A(TSA)、DNA去甲基化酶抑制剂5-氮杂-2-脱氧胞(Aza)刺激M1、M2巨噬细胞后,检测TNF-α、IL-6、Arginase、Fizz-1 mRNA水平表达的变化。结果 RAW264.7细胞经LPS刺激8 h极化为M1巨噬细胞;RAW264.7细胞经IL-4体外刺激24 h极化为M2巨噬细胞。小鼠BMDM在LPS、IL-4刺激下,分别极化为M1、M2巨噬细胞,改变体外刺激条件,M1巨噬细胞可重分化为M2样巨噬细胞,M2巨噬细胞可重分化为M1样巨噬细胞,M1样巨噬细胞和M2巨噬细胞是介于M1、M2中间状态的2种巨噬细胞;药物TSA、Aza的加入使M1、M2中特定标记基因TNF-α、IL-6、Arginase、Fizz-1 mRNA水平表达增加。结论巨噬细胞的功能极化具有可塑性,巨噬细胞的极化可能与染色质状态的改变有关。     

巨噬细胞极化与动脉粥样硬化斑块稳定性的研究进展

动脉粥样硬化是一种慢性炎症性疾病,其中粥样斑块的形成与演变直接影响疾病进程。斑块中纤维帽变薄、脂核区增大、胶原降解酶增多等都会影响斑块稳定性,导致斑块破裂,并进一步形成血栓,最终引发一系列心血管疾病。巨噬细胞泡沫化后构成粥样斑块中的重要成分。近年研究发现巨噬细胞不同表型占比影响斑块稳定性。本文就巨噬细胞表型、巨噬细胞极化对斑块稳定性的影响及相关机制进行综述。     

Aire 对巨噬细胞极化影响的研究

目的:研究自身免疫调节因子(Aire)对巨噬细胞极化的影响。方法:分别用LPS、IL-4 以及LPS 联合免疫复合物刺激小鼠单核巨噬细胞系RAW264郾7 细胞、稳定表达GFP-Aire 的RAW264.7 细胞(A33-3) 细胞和稳定表达GFP 的RAW264.7 细胞(C1-6),使其向M1(LPS)、M2a(IL-4)和M2b(LPS 联合免疫复合物)型巨噬细胞极化。通过Real-time PCR 检测各组细胞中M1 型巨噬细胞特征分子IL-1、iNOS 和IL-6,M2a 型特征分子Arg-1 和M2b 型特征分子IL-10 的表达水平,研究Aire 对各种类型巨噬细胞极化的影响。结果:LPS 在0.5 g/ ml 浓度时,RAW264.7 细胞中M1 型巨噬细胞产物IL-1 、iNOS和IL-6 基因表达量最高;而IL-4 以及LPS 联合免疫复合物的刺激作用有显著的剂量依赖性,都在浓度最高时RAW264.7 细胞中Arg1(M2a)和IL-10(M2b)基因表达量最高。LPS 刺激后,A33-3 细胞中IL-1 和iNOS 表达水平明显高于C1-6 细胞,IL-6 则相反;IL-4 及LPS 联合免疫复合物刺激后,A33-3 细胞中Arg1 和IL-10 的表达水平明显低于C1-6 细胞。结论:Aire 可能促进巨噬细胞向M1 极化,同时抑制其向M2a 和M2b 极化。     

小鼠骨髓来源巨噬细胞体外培养及极化相关实验方法的建立

目的 建立小鼠骨髓来源巨噬细胞体外培养,并将其极化为M1和M2型巨噬细胞的方法.方法 获取小鼠骨髓细胞,以GM-CSF诱导其中单核细胞向巨噬细胞分化发育,并辅以LPS和IFN-γ以及IL-4刺激巨噬细胞分别向M1型和M2型分化.采用流式细胞术、实时定量PCR和ELISA的实验检测极化后细胞内以及细胞培养上清中的标志性细胞因子如IL-12、IL-10、Argl、Yml、MMR等的表达情况.结果 形态学观察发现骨髓获取的细胞经诱导分化后呈现巨噬细胞特征性的贴壁形态;流式细胞术行胞内染色表明,极化后的M1型与M2型巨噬细胞各自表达其特征性的细胞因子IL-12和Argl;实时定量PCR和ELISA分别检测所培养细胞胞内以及培养上清中的细胞因子,结果表明所刺激的M1型巨噬细胞高表达IL-12、iNOS、TNF-α等炎性因子,而M2型巨噬细胞表达MMR、Argl、Yml等标志因子.结论 建立了稳定的M1和M2型巨噬细胞体外培养体系.     

巨噬细胞极化信号通路及其调控机制研究进展

巨噬细胞是一类具有异质性和可塑性的免疫细胞,由单核细胞分化而来,在不同环境下可极化为不同的表型,分化中的巨噬细胞可位于极端分化的两型中的任意阶段。巨噬细胞在此极化过程中涉及较多的信号通路和转录调控,故本文将介绍具体巨噬细胞极化的通路及调控因子。     

Epigenetic control of macrophage polarization

Epigenetic control of gene expression is critical for cellular differentiation and development. Macrophage development, polarization and activation are also controlled by DNA and histone modifications. This Viewpoint summarizes the recent findings on the role of histone modifications regulating macrophage polarization toward M1 and M2 subtypes.     

信号转导及转录激活因子家族分子在巨噬细胞极化调控中的作用研究进展

巨噬细胞在调控炎症及免疫反应,维持免疫稳态中发挥关键的作用.不同微环境条件下,巨噬细胞功能出现异质性.其可以极化为经典活化(M1)或替代活化(M2)两种不同的极化类型,分别发挥促炎或抑炎的功能.众所周知,许多调控分子参与了巨噬细胞的极化调控过程.在众多的极化调控分子中,信号转导及转录激活因子(Stats)家族是一类最主要的调控分子.Stats家族有7个成员,即Stat1、Stat2、Stat3、Stat4、Stat5a、Stat5b和Stat6.它们结构相似,但功能不同.目前已经明确,Stats分子在机体炎症应答中发挥重要的作用,调控着巨噬细胞的极化进程.     

New vistas on macrophage differentiation and activation

Plasticity and heterogeneity are hallmarks of myelomonocytic differentiation and polarized activation. Evidence published in this issue of the European Journal of Immunology, together with other recent data, add new elements and perspectives to the current understanding of mononuclear phagocyte differentiation and activation and are discussed in this Commentary.     

4种大鼠睾丸移植模型的建立方法与比较

目的: 比较4种大鼠睾丸移植模型的建立方法。方法: 建立4种不同术式的大鼠睾丸移植模型各10例，分别比较其血管重建时间、即时通畅率、显微外科技术要求及术后1个月植睾血供情况和功能。结果: 40例受体大鼠存活均超过30 d，4种方法的血管重建时间和显微外科技术难易程度有所不同，但开放血流后即时通畅率及术后1个月植睾血供情况和血清睾酮水平相互比较无明显差异。 结论: 4种方法均可选择性地用于不同解剖类型的大鼠睾丸移植的实验研究。     

巨噬细胞极化在心血管疾病中的作用

心血管病,尤其是急性心肌梗死和收缩性心功能衰竭已成为西方国家患者死亡的主要原因,在发展中国家也呈明显上升趋势.缺血性的心脏病已经成为普遍现象,是引起病人死亡的主要原因.尽管早期血管再建和药物治疗能够明显提高心肌梗死后的生存率,但仍有大量病人发展成心力衰竭.巨噬细胞除了具有免疫防御和维持组织稳态功能,还在心肌梗死诱导的病理生理过程中发挥重要作用.巨噬细胞的亚群已被证实参与心血管疾病(动脉粥样硬化、心肌梗死、心肌缺血、心肌纤维化)的发生和发展,在心脏损伤和心肌重塑中有重要作用,研究基于巨噬细胞调控治疗心血管疾病的治疗策略很有价值.     

各种不同慢性食管反流模型制备手术后大鼠死因分析

目的：为提高慢性食管反流(CER)动物模型制备的成功率，通过对造模术后非预期死亡动物死因进行分析，以探索各种不同类型CER理想动物模型的制备方法。 方法:选取SD大鼠120只，其中20只作为假手术（SO）对照组，100只采用不同术式分别制备十二指肠胃食管反流（DGER）、单纯胃食管反流（GER）和十二指肠食管反流（DER）3种类型CER动物模型。并对术后非预期死亡动物进行尸体解剖分析。 结果:120只SD大鼠中术后非预期死亡37只（30.8%），其中DGER组18只（38.3%）；GER组中幽门部分缝扎+贲门肌切开术后9只死亡8只，改行食管胃底侧侧吻合术后20只死亡1只（5%）；DER组中食管空肠侧侧吻合术后3只均死亡，改行食管十二指肠侧侧吻合术后21只死亡7只（33.3%）；SO组20只中未见死亡。尸解分析死亡原因有梗阻、感染、窒息、出血、吻合口漏和穿孔等。 结论:制备CER大鼠模型不同类型、不同术式死亡率各异,某些术式对手术要求较高。因此，不但要选择合理的术式，以制备符合研究需要的理想模型，还要采取适当措施预防术后并发症降低非预期死亡率，以提高模型制备成功率。     

Controlled release of cytokines using silk-biomaterials for macrophage polarization

Polarization of macrophages into an inflammatory (M1) or anti-inflammatory (M2) phenotype is important for clearing pathogens and wound repair, however chronic activation of either type of macrophage has been implicated in several diseases. Methods to locally control the polarization of macrophages is of great interest for biomedical implants and tissue engineering. To that end, silk protein was used to form biopolymer films that release either IFN-γ or IL-4 to control the polarization of macrophages. Modulation of the solubility of the silk films through regulation of β-sheet (crystalline) content enabled a short-term release (4–8 h) of either cytokine, with smaller amounts released out to 24 h. Altering the solubility of the films was accomplished by varying the time that the films were exposed to water vapor. The released IFN-γ or IL-4 induced polarization of THP-1 derived macrophages into the M1 or M2 phenotypes, respectively. The silk biomaterials were able to release enough IFN-γ or IL-4 to repolarize the macrophage from M1 to M2 and vice versa, demonstrating the well-established plasticity of macrophages. High β-sheet content films that are not soluble and do not release the trapped cytokines were also able to polarize macrophages that adhered to the surface through degradation of the silk protein. Chemically conjugating IFN-γ to silk films through disulfide bonds allowed for longer-term release to 10 days. The release of covalently attached IFN-γ from the films was also able to polarize M1 macrophages in vitro. Thus, the strategy described here offers new approaches to utilizing biomaterials for directing the polarization of macrophages.     

Convergent pathways of macrophage polarization: The role of B cells

The construction of an inflammatory microenvironment provides the fuel for cancer development and progression. Hence, solid tumors promote infiltration of leukocyte populations, among which tumor‐associated macrophages (TAM) represent a paradigm for cancer‐promoting inflammation. TAM orchestrate various aspects of cancer, including diversion and skewing of adaptive responses, cell growth, angiogenesis, matrix deposition and remodelling, the construction of a metastatic niche and actual metastasis, response to hormones and chemotherapeutic agents. Several lines of evidence indicate that TAM show a remarkable degree of plasticity and functional heterogeneity, suggesting that during tumor progression macrophages undergo a phenotypic “switch”, eventually exhibiting the alternatively activated, “M2”, phenotype that is associated with immunosuppression, promotion of tumor angiogenesis and metastasis. Although recent studies have attempted to address the role of microenvironmental signals on TAM “reprogramming”, the interplay between innate and adaptive immunity is emerging as a crucial step of this event. In this issue of the European Journal of Immunology, a study demonstrates that B1 lymphocytes expressing IL‐10 play a key role in promoting a pro‐tumoral M2‐biased phenotype of macrophages. This article defines a new in vivo pathway of macrophage polarization and suggests that targeting B cells is a possible therapeutic intervention to reinstate anti‐cancer functions by TAM.     

Cytokine polarization in miliary and pleural tuberculosis

Cytokines were measured in patients with pleural effusion and miliary tuberculosis (TB). Patients with pleural effusion had significantly higher interferon-gamma (IFN-) levels (P < 0.001) in their pleural fluid as compared to that of peripheral blood of the same patients, thus exhibiting localization of predominantly Th1-type immunity in the pleural fluid. On the contrary, patients with miliary TB had higher IFN- levels in the peripheral blood as compared to their bronchoalveolar lavage fluid. Moreover, the median IFN-:IL-4 ratio in the peripheral blood of miliary TB patients was two-fold higher as compared to bronchoalveolar lavage fluid, suggesting that the cytokine profile at the disease site is skewed toward a Th2-like bias. Further, flow cytometry data revealed a significantly higher (P < 0.001) percentage of CD4⁺ pleural fluid lymphocytes expressing IFN-, whereas in the miliary TB, a nine-fold higher percentage of lymphocytes in bronchoalveolar lavage fluid expressed IL-4 in comparison with their peripheral CD4 T cells. Our data indicate, respectively, a Th1-like and Th2-like response in tuberculous pleural effusion and miliary TB, suggesting that these clinical forms of extrapulmonary tuberculosis probably reflect the extreme ends of a Th1–Th2 spectrum of the disease.     

In vitro response of macrophage polarization to a keratin biomaterial

Macrophage response to biomaterials is emerging as a major focus in tissue repair and wound healing. Macrophages are able to differentiate into two distinct states, eliciting divergent effects. The M1 phenotype is considered pro-inflammatory and up-regulates activity related to tissue destruction, whereas the M2 phenotype is considered anti-inflammatory and supports tissue remodeling. Both are necessary but a fine balance must be maintained as dysregulation of naïve macrophages to M1 or M2 polarization has been implicated in several disease and injury models, and has been suggested as a potential cause for poor outcomes. Keratin biomaterials have been shown using different animal models to promote regeneration in several tissues. A potential common mechanism may be the general capability for keratin biomaterials to elicit beneficial inflammatory responses during the early stages of regeneration. In the present study, a keratin biomaterial was utilized in vitro to examine its effects on polarization toward one of these two macrophage phenotypes, and thus its role in inflammation. Exposure of a monocytic cell line to keratin biomaterial substrates was shown to bias macrophages toward an M2 phenotype, while a collagen control surface produced both M1 and M2 macrophages. Furthermore, keratin treatment was similar to the M2 positive control and was similarly effective at down-regulating the M1 response. Keratin biomaterial influenced greater production of anti-inflammatory cytokines and decreased amounts of pro-inflammatory cytokines. The use of a keratin biomaterial in regenerative medicine may therefore provide additional benefit by regulating a positive remodeling response.