Systems-Level Proteomics Evaluation of Microglia Response to Tumor-Supportive Anti-Inflammatory Cytokines.
Systems-Level Proteomics Evaluation of Microglia Response to Tumor-Supportive Anti-Inflammatory Cytokines.
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DOI：
10.3389/fimmu.2021.646043
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发表时间：
2021
影响因子：
7.3
通讯作者：
Lazar IM
中科院分区：
文献类型：
--
作者：
Ahuja S;Lazar IM
小胶质细胞保护中枢神经系统免受损伤和病原体的侵害，并且在某些有害刺激的存在下能够诱导疾病依赖性炎症反应。然而，当暴露于抗炎细胞因子时，这些细胞具有从炎性表型转变为免疫抑制表型的能力。癌细胞利用这种特性来逃避免疫系统，并引发促进肿瘤附着和生长的抗炎微环境。用质谱和蛋白质组学技术探索了在小胶质细胞中响应于从癌细胞释放的抗炎细胞因子而激活的肿瘤支持生物学过程。用IL-4、IL-13、IL-10、TGFβ和CCL 2的混合物处理血清耗尽和非耗尽的人小胶质细胞（HMC 3）。通过LC-MS/MS分析细胞蛋白质提取物。使用功能注释聚类工具，将在苦参碱处理的和未处理的细胞之间显示丰度变化的统计学显著蛋白质映射到它们的生物网络和途径。HMC 3细胞的蛋白质组学分析能够鉴定约10，000种蛋白质。用抗炎细胞因子刺激导致激活不同但整合的蛋白质簇，其触发下游许多促肿瘤生物过程。观察到的变化可分为四大类，即，线粒体基因表达、ECM重塑、免疫应答和受损的细胞周期进程。细胞内免疫激活主要由MAPK、STAT、TGFβ、NF κ B和整合素信号转导通路介导。丰富的胶原蛋白形成沿着额外受体、基质组分、生长因子、蛋白酶和蛋白酶抑制剂的表达，表明支持细胞-细胞和细胞-基质粘附的ECM重塑过程。整合素及其调节剂的过度表达反映了将ECM重组与支持细胞迁移的细胞骨架重排联系起来的信号传导过程。抗原加工/呈递由HLA I类组织相容性抗原表示，并与上调的蛋白酶体亚单位、囊泡/病毒转运和分泌过程相关。免疫抑制和促血管生成趋化因子，以及抗血管生成因子，检测到低丰度。未观察到明显的促炎、趋化或吞噬趋势，然而，某些受体、信号传导和ECM蛋白的表达表明存在此类能力。用抗炎细胞因子刺激的HMC 3细胞的综合蛋白质组分析揭示了通过微环境依赖性生物学机制支持脑中癌症发展的小胶质细胞表型谱。
Microglia safeguard the CNS against injuries and pathogens, and in the presence of certain harmful stimuli are capable of inducing a disease-dependent inflammatory response. When exposed to anti-inflammatory cytokines, however, these cells possess the ability to switch from an inflammatory to an immunosuppressive phenotype. Cancer cells exploit this property to evade the immune system, and elicit an anti-inflammatory microenvironment that facilitates tumor attachment and growth. The tumor-supportive biological processes that are activated in microglia cells in response to anti-inflammatory cytokines released from cancer cells were explored with mass spectrometry and proteomic technologies. Serum-depleted and non-depleted human microglia cells (HMC3) were treated with a cocktail of IL-4, IL-13, IL-10, TGFβ, and CCL2. The cellular protein extracts were analyzed by LC-MS/MS. Using functional annotation clustering tools, statistically significant proteins that displayed a change in abundance between cytokine-treated and non-treated cells were mapped to their biological networks and pathways. The proteomic analysis of HMC3 cells enabled the identification of ~10,000 proteins. Stimulation with anti-inflammatory cytokines resulted in the activation of distinct, yet integrated clusters of proteins that trigger downstream a number of tumor-promoting biological processes. The observed changes could be classified into four major categories, i.e., mitochondrial gene expression, ECM remodeling, immune response, and impaired cell cycle progression. Intracellular immune activation was mediated mainly by the transducers of MAPK, STAT, TGFβ, NFKB, and integrin signaling pathways. Abundant collagen formation along with the expression of additional receptors, matrix components, growth factors, proteases and protease inhibitors, was indicative of ECM remodeling processes supportive of cell-cell and cell-matrix adhesion. Overexpression of integrins and their modulators was reflective of signaling processes that link ECM reorganization with cytoskeletal re-arrangements supportive of cell migration. Antigen processing/presentation was represented by HLA class I histocompatibility antigens, and correlated with upregulated proteasomal subunits, vesicular/viral transport, and secretory processes. Immunosuppressive and proangiogenic chemokines, as well as anti-angiogenic factors, were detectable in low abundance. Pronounced pro-inflammatory, chemotactic or phagocytic trends were not observed, however, the expression of certain receptors, signaling and ECM proteins indicated the presence of such capabilities. Comprehensive proteomic profiling of HMC3 cells stimulated with anti-inflammatory cytokines revealed a spectrum of microglia phenotypes supportive of cancer development in the brain via microenvironment-dependent biological mechanisms.
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影响因子：
4
作者：
Fitzgerald, Daniel P.;Palmieri, Diane;Hua, Emily;Hargrave, Elizabeth;Herring, Jeanne M.;Qian, Yongzhen;Vega-Valle, Eleazar;Weil, Robert J.;Stark, Andreas M.;Vortmeyer, Alexander O.;Steeg, Patricia S.
通讯作者：
Steeg, Patricia S.
DOI：
10.1073/pnas.1716305114
发表时间：
2017-12-26
影响因子：
11.1
作者：
Albert S;Schaffer M;Beck F;Mosalaganti S;Asano S;Thomas HF;Plitzko JM;Beck M;Baumeister W;Engel BD
通讯作者：
Engel BD
影响因子：
9.3
作者：
Cherry JD;Olschowka JA;O'Banion MK
通讯作者：
O'Banion MK
DOI：
10.4161/jkst.20045
发表时间：
2012-04-01
期刊：
JAK-STAT
影响因子：
--
作者：
Avalle L;Pensa S;Regis G;Novelli F;Poli V
通讯作者：
Poli V
影响因子：
3.7
作者：
Fodelianaki, Georgia;Lansing, Felix;Alexaki, Vasileia Ismini
通讯作者：
Alexaki, Vasileia Ismini