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尖峰蛋白、巨噬细胞和燃烧的炎症：涡轮癌的另一个驱动因素

斯派克蛋白对巨噬细胞的极化作用可能有助于解释涡轮癌诊断的突然上升，因为它似乎是火上浇油。

沃尔特·M·栗子

6月30日

The Spike Protein, Macrophages and Smoldering Inflammation: Yet Another Driver of Turbocancers
The Spike Protein’s polarizing effect on Macrophages may help explain the sudden rise in turbocancer diagnoses as it appears to be gasoline on the fire.
WALTER M CHESNUT
JUN 30

https://open.substack.com/pub/wmcresearch/p/the-spike-protein-macrophages-and-972

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Tumor-associated macrophages favor tumor development through different functions. TAMs have various roles in tumorigenesis and as such, interact closely with cancer cells and the TME. TAMs create a pro-tumoral immune environment by: inactivating cytotoxic T cells through PD-L1 expression; and producing various cytokines to recruit regulatory T cells (IL-6, IL-10 and TGF-ß) and create an inflammatory milieu (IL-6, IL- 1ß, CXCL8). TAMs shape the extracellular matrix by producing proteases such as matrix metalloproteinases or cathepsins that degrade collagen fibers and ensure their turnover. TAMs also produce cross-linking enzymes that modulate the stiffness of the extracellular matrix. TAM-secreted VEGF promotes angiogenesis that facilitates tumor progression as well as metastasis. TAMs migrate with cancer cells to blood vessel where they create openings known as “TMEM doorways”, allowing cancer cells to disseminate in the circulation. Finally, TAMs produce TGF-ß and CCL18 that have a role in epithelia to mesenchymal transition, allowing cancer cells to migrate. Mesenchymal cells promote TAM activation through GM-CSF production.

The Spike Protein has been associated with a very cryptic and sinister symptom of PASC. That is the presence of low-level cytokines, causing an almost imperceptible level of chronic inflammation.

In this cross-sectional study, blood samples were obtained from three different sites in Australia from individuals with i) a resolved SARS-CoV-2 infection (and no persistent symptoms i.e. ‘Recovered’), ii) individuals with prolonged PASC-CVS and iii) SARS-CoV-2 negative individuals. Individuals with PASC-CVS, relative to Recovered individuals, had a blood transcriptomic signature associated with inflammation. This was accompanied by elevated levels of pro-inflammatory cytokines (IL-12, IL-1β, MCP-1 and IL-6) at approximately 18 months post-infection. These cytokines were present in trace amounts, such that they could only be detected with the use of novel nanotechnology. Importantly, these trace-level cytokines had a direct effect on the functionality of pluripotent stem cell derived cardiomyocytes in vitro. This effect was not observed in the presence of dexamethasone. Plasma proteomics demonstrated further differences between PASC-CVS and Recovered patients at approximately 18 months post-infection including enrichment of complement and coagulation associated proteins in those with prolonged cardiovascular symptoms. Together, these data provide a new insight into the role of chronic inflammation in PASC-CVS and present nanotechnology as a possible novel diagnostic approach for the condition.

Cardiovascular symptoms of PASC are associated with trace-level cytokines that affect the function of human pluripotent stem cell derived cardiomyocytes
https://www.biorxiv.org/content/10.1101/2024.04.11.587623v1.full

Why is this important? Because it is this very low-level inflammation which can induce tumors. The Spike Protein’s interaction with macrophages almost certainly contributes to this type of inflammation. We notice a pervasive induction of low-level inflammation throughout the body - induced by the Spike Protein – and the additional presence of macrophages polarizing to the M1 phenotype. Please see my previous posts which document how the Spike Protein activates and polarizes macrophages.

The type of inflammation associated with increased cancer risk due to chronic infection or persistent irritation is often called “smoldering inflammation” (Mantovani and Sica, 2010). This nomenclature is used because the inflammation is low grade without overt clinical consequences. Activated macrophages are central to this type of immune response and work in concert with other immune cells (Balkwill et al., 2005). It has been hypothesized that these immune cells produce a mutagenic environment (Pang et al., 2007) by generating both reactive nitrogen and oxygen species. NO in particular reacts with peroxidates to give nitrosoperoxycarbonate and this reaction is a major driver of the chemistry of inflammation. This highly reactive compound and other products cause mutations in the adjacent epithelial cells (Meira et al., 2008; Pang et al., 2007). In addition, there is evidence that the inflammatory microenvironment also promotes genetic instability within the developing tumor epithelial cells (Colotta et al., 2009). In either case, the mutations are fixed after replication of the epithelial cells, a process that is stimulated by growth factors synthesized by the infiltrating or resident immune cells that include macrophages. These growth-promoting effects on tumors are caused by the production of IL-6 in hepatocellular carcinoma (HCC) (Lin and Karin, 2007; Naugler et al., 2007) and TNFα (Karin et al., 2006) and IL-6 in colitis associated cancers (Grivennikov et al., 2009).

Macrophage Diversity Enhances Tumor Progression and Metastasis
https://pmc.ncbi.nlm.nih.gov/articles/PMC4994190/

Indeed, the activated macrophage is associated with tumor initiation.

The macrophage phenotype associated with cancer initiation and promotion is comparable to the “activated” one (Gordon, 2003). However, once initiated and the tumors progress towards malignancy, the macrophage phenotype changes from the “inflammatory” type to one that resembles macrophages that promote tissue formation during development (Figure 1) (Pollard, 2004, 2009).

Macrophage Diversity Enhances Tumor Progression and Metastasis
https://pmc.ncbi.nlm.nih.gov/articles/PMC4994190/

Now, here is where it becomes really interesting. Readers may recall my discussions about the Spike Protein and its interactions with the Extracellular Matrix (ECM). Lo and behold, macrophages perform the same functions – most likely in tandem. Please note the following macrophage properties are tailor-made for developing a turbocancer. It is the proverbial “throwing gasoline on the fire.”

TAMs (Tumor Associated Macrophages) are also involved in active ECM remodeling, collaborating notably with cancer-associated fibroblasts (CAFs) to promote tumor cell intravasation [69]. Indeed, tumors often display a dense ECM that notably impairs drug penetration, limiting treatment efficacy and resulting in more metastases [70, 71].

Roles of macrophages in tumor development: a spatiotemporal perspective
https://www.nature.com/articles/s41423-023-01061-6

And now, unfortunately, for the grand finale. We can see with absolute clarity that SARS-CoV-2 is almost certainly an oncogenic virus par excellence. Enter the endothelium – and metastases.

EMT and ECM remodeling precede the intravasation of tumor cells into the circulation and their subsequent dissemination to distal organs. This key event in metastasis formation occurs at sites known as “tumor microenvironment metastasis (TMEM) doorways”, characterized by the dynamic association between one endothelial cell, one TAM and one cancer cell [80,81,82].

Roles of macrophages in tumor development: a spatiotemporal perspective
https://www.nature.com/articles/s41423-023-01061-6

The picture that forms is one of a two-pronged attack by the Spike Protein. It attacks the endothelium (to open lines, as we say in chess) and then “uses” our body’s own immune cells to destroy tissues and organs – and initiate chronic diseases. I will continue to work on understanding this pathogen and finding ways to combat it. Thank you, as always, for your readership, dialogue, and support. 尖峰蛋白，巨噬细胞和燃烧的炎症：涡轮癌的另一圈动手因素斯克蛋白对巨噬细胞的极化 Walter M Chesnut 6月30日在APP肿瘤相关巨噬细胞中阅读，有利于不同功能的肿瘤发展。 TAMS在肿瘤发生中具有各种作用，因此与癌细胞和TME紧密相互作用。 TAMS通过：通过PD-L1表达灭活细胞毒性T细胞来产生促肿瘤免疫环境; 并产生各种细胞因子募集调节性T细胞（IL-6，IL-10和TGF-β），并产生炎症Milieu（IL-6，IL-1ß，CXCL8）。 TAMS通过生产蛋白酶如基质金属蛋白酶或抑制胶原纤维的组织蛋白酶而形成细胞外基质，并确保其转换。 TAMS还产生交联酶，其调节细胞外基质的刚度。 TAM分泌的VEGF促进血管生成，促进肿瘤进展以及转移。 TAMS将癌细胞迁移到血管，在那里他们创造出称为“TMEM门道”的开口，允许癌细胞在循环中传播。 最后，TAMS产生TGF-β和CCL18，其在上皮细胞转化中具有作用，允许癌细胞迁移。 间充质细胞通过GM-CSF生产促进TAM活化。 穗蛋白已与PASC的一个非常神秘和阴险的症状有关。 这是低水平细胞因子的存在，导致几乎是难以察觉的慢性炎症水平。 在这种横截面研究中，从澳大利亚的三个不同部位从澳大利亚的三种不同的位点从澳大利亚的血液样本中获得了一个已解决的SARS-COV-2感染（并且没有持续的症状，即“恢复”），II）具有延长的PASC-CVS的个体和 具有pasc-cvs的个体，相对于回收的个体，与炎症有关的血液转录组签名。 这伴随着感染后约18个月的促炎细胞因子（IL-12，IL-1β，MCP-1和IL-6）的升高。 这些细胞因子以痕量存在，使得它们只能通过使用新颖的纳米技术来检测。 重要的是，这些痕量细胞因子对体外具有直接影响多能干细胞衍生心肌细胞的功能性。 在地塞米松存在下未观察到这种效果。 血浆蛋白质组学在感染后大约18个月的患者中表现出PPASC-CVS和恢复患者之间的进一步差异，包括富含心血管症状的浓缩和凝血相关蛋白质的富集。 这些数据在一起，对慢性炎症在PASC-CVS中的作用提供了新的洞察力，并将纳米技术作为条件的可能的新诊断方法。 PASC的心血管症状与痕量细胞因子相关，影响人类多能干细胞衍生心肌细胞…2014 因为它是这种非常低水平的炎症，可以诱导肿瘤。 穗蛋白与巨噬细胞的相互作用几乎肯定有助于这种类型的炎症。 我们注意到整个身体的低水平炎症诱导 - 穗蛋白诱导的低水平炎症 - 以及巨噬细胞对M1表型偏振的额外存在。 请参阅我以前的帖子，该帖子记录着尖峰蛋白的激活和偏热巨噬细胞。 由于慢性感染或持续刺激而增加的癌症风险增加的炎症类型通常被称为“闷烧炎症”（Mantovani和Sica，2010）。 使用该命名法，因为没有明显临床后果的炎症是低级的。 活化的巨噬细胞是这种免疫反应的核心，与其他免疫细胞一起工作（Balkwill等，2005）。 已经假设这些免疫细胞通过产生反应性氮和氧物质产生致致诱变环境（Pang等，2007）。 特别是没有用过氧化物反应，得到亚硝基氟氧基碳酸酯，并且该反应是炎症化学的主要驱动器。 这种高反应性化合物和其他产品导致相邻上皮细胞中的突变（Meira等，2008; Pang等，2007）。 此外，有证据表明炎性微环境还促进了显影肿瘤上皮细胞（Colotta等，2009）内的遗传不稳定。 在任何一种情况下，突变在上皮细胞复制后固定，该方法被包括巨噬细胞的浸润或常规免疫细胞合成的生长因子刺激。 这些对肿瘤的增长效果是由肝细胞癌（HCC）中IL-6的产生引起的（Lin和Karin，2007; Naugler等，2007）和TNFα（Karin等，2006）和 巨噬细胞分化增强肿瘤进展和转移…活化的巨噬细胞与肿瘤开始有关 与癌症启动和促进相关的巨噬细胞表型与“激活”一体（Gordon，2003）相当。 然而，一旦发起和肿瘤对恶性肿瘤的进展，巨噬细胞表型从“炎症”类型变为一种类似于促进开发组织形成的巨噬细胞的巨噬细胞（图1）（Pollard，2004,2009）。 巨噬细胞多样性增强肿瘤进展和转移…这是它变得非常有趣的地方。 读者可能会记住我对穗蛋白质的讨论及其与细胞外基质（ECM）的相互作用。 Lo和Pheold，巨噬细胞执行相同的功能 - 最有可能在串联中。 请注意，以下巨噬细胞属性是为开发涡轮机而定制的。 这是众所周知的“在火上投掷汽油” TAMS（肿瘤相关的巨噬细胞）也参与活性ECM重塑，特别是与癌症相关的成纤维细胞（CAF）进行协作以促进肿瘤细胞介绍[69]。 实际上，肿瘤经常显示致密的ECM，明显损害药物渗透，限制治疗效果并导致更多的转移[70,71]。 巨噬细胞在肿瘤发展中的作用：时空透视…现在，遗憾的是，对于大决赛。 我们可以通过绝对清晰地看到SARS-COV-2几乎肯定是一种致癌病毒卓越。 进入内皮和转移。 EMT和ECM重塑在肿瘤细胞的介质前进到循环中的循环及其随后的远端器官的散发。 转移形成中的这种关键事件发生在称为“肿瘤微环境转移（TMEM）门口”的位点，其特征在于一种内皮细胞，一个TAM和一个癌细胞之间的动态关联[80,81,82]。 巨噬细胞在肿瘤发展中的作用：…攻击内皮（如棋子所说，打开线条），然后“使用”我们的身体自己的免疫细胞破坏组织和器官 - 并开始慢性疾病。 我将继续努力了解这条病原体并找到打击它的方法。 衷心感谢您的读者，对话和支持。