RNF128

急性肺损伤(ALI)和急性呼吸窘迫综合征(ARDS)是以严重的肺部炎症、肺泡毛细血管屏障受损和肺水肿为特征的危及生命的呼吸系统疾病，死亡率高。 急性肺损伤(ALI)和急性呼吸窘迫综合征(ARDS)是以严重的肺部炎症、肺泡毛细血管屏障受损和肺水肿为特征的危及生命的呼吸系统疾病，死亡率高。ALI发生发展的分子机制尚未完全阐明，但肺泡巨噬细胞和中性粒细胞在ALI的发病机制中起着关键作用。 激活的中性粒细胞和肺泡巨噬细胞释放过量的促炎细胞因子，如肿瘤坏死因子-α(肿瘤坏死因子-α)、白介素6(IL-6)和白介素1-β(IL-1β)，并触发局部炎症反应，损害肺上皮和内皮细胞。髓过氧化物酶(MPO)是一种含血的天青颗粒酶，主要表达于中性粒细胞。 活化的中性粒细胞释放MPO，增强ALI时的炎症反应和组织损伤。内毒素是革兰氏阴性细菌外膜的主要成分，可促进ALI。内毒素刺激后，免疫细胞激活TLR4依赖的信号通路，释放多种细胞因子。TLR4可通过抑制IκB蛋白和促进促炎细胞因子表达来激活转录因子核因子-κB(NF-κB)。尽管研究表明TLR4信号与ALI的进展有关，但其潜在的分子机制仍有待阐明。 图片来源：https://doi-org.libproxy1.nus.edu.sg/10.1038/s41419-023-05890-1 近日，来自中国台湾国防医学中心的研究者们在Cell Death and Disease杂志上发表了题为“RNF128 regulates neutrophil infiltration and myeloperoxidase functions to prevent acute lung injury”的文章，该研究揭示了RNF128调节中性粒细胞浸润和髓过氧化物酶功能预防急性肺损伤。 急性肺损伤(ALI)以严重的肺部炎症、肺泡-毛细血管屏障破坏和肺水肿为特征。因此，建立有效的治疗靶点对ALI的预防至关重要。本研究报道了RNF128在调节脂多糖诱导的ALI中的一个新功能。 RNF128基因缺陷小鼠肺损伤严重，免疫细胞浸润增加。体外实验表明，RNF128通过与髓过氧化物酶(MPO)结合并降低其水平和活性来抑制中性粒细胞的激活。此外，RNF128通过与TLR4相互作用，靶向TLR4的降解，抑制NF-κB的激活，从而减少促炎细胞因子，从而调节肺泡巨噬细胞的激活和中性粒细胞的浸润。 本研究的结果首次证明RNF128在中性粒细胞和肺泡巨噬细胞中分别是MPO和TLR4的负调节因子。而AAV9介导的RNF128过表达可减轻肺组织损伤，减少炎性细胞浸润。 RNF128过表达可减轻内毒素诱导的肺损伤 图片来源：https://doi-org.libproxy1.nus.edu.sg/10.1038/s41419-023-05890-1 综上所述，本研究确定RNF128是一个潜在的ALI调节因子。这一调节的潜在机制也得到了阐明。本研究的发现将成为开发新的ALI治疗策略的极好平台。（生物谷 Bioon.com） 参考文献 Pei-Yao Liu et al. RNF128 regulates neutrophil infiltration and myeloperoxidase functions to prevent acute lung injury. Cell Death Dis. 2023 Jun 21;14(6):369. doi: 10.1038/s41419-023-05890-1.

New research shows that gut bacteria boost the progression of leukemia caused by a retrovirus in mice by enhancing the activity of genes that tamp down the immune response. Gut bacteria have a profound impact on health by aiding digestion, providing nutrients and metabolites, and working with the immune system to fend off pathogens. Some gut bacteria, however, have been implicated in progression of cancers of the gut and associated organs. A new study by researchers from the University of Chicago shows that some commensal bacteria promote the development of leukemia caused by the murine leukemia virus (MuLV) by suppressing the animal's adaptive anti-tumor immune response. When both the virus and commensal bacteria are present in mice, three genes known as negative immune regulators are expressed more, or upregulated, which in turn tamps down the immune response that would otherwise kill the tumor cells. Two of these three negative immune regulators are also known to be indicators of poor prognosis for humans with some forms of cancer. "These two negative immune regulators have been really well documented to be poor prognostic factors in some human cancers, but nobody knew why," said Tatyana Golovkina, PhD, Professor of Microbiology at UChicago and senior author of the study. "Using a mouse model of leukemia, we found that the bacteria contribute to upregulation of these negative immune regulators, allowing developing tumors to escape recognition by the immune system." Results of the research, "Gut commensal bacteria enhance pathogenesis of a tumorigenic murine retrovirus," were published September 13 in Cell Reports. Cancer is usually thought to be the result of spontaneous mutations that cause cells to grow and multiply out of control, forming tumors. In 1910, a pathologist named Peyton Rous took a sample from cancerous tumor in a chicken and injected it into a healthy bird, which developed cancer as well. His discovery was dismissed at the time, but researchers later discovered that the cancer was transmitted by a retrovirus. This discovery prompted more research and subsequent identification of numerous retroviruses causing various types of cancer. Some cancer-causing retroviruses take advantage of gut microbes to spread and replicate. For example, in a 2011 study, Golovkina and her team found that a virus that causes mammary tumors in mice depends on gut bacteria, enabling the virus to block the immune responses from recognizing and eliminating infected cells. Thus, the microbes help the virus replicate and as a result, tumors develop. In the new study, the researchers wanted to see if commensal bacteria affected the development of a virus-induced cancer in another way besides assisting its replication. They used germ-free (GF) mice that had been raised in a special facility so they had no microbes, and specific pathogen free (SPF) mice that don't have any pathogenic microbes that could causes disease but do have common commensal microbes, including bacteria that normally populate the gut. GF and SPF mice were both infected with the murine leukemia virus (MuLV). While the virus infected and replicated equally well in both types of mice, only SPF mice developed high-frequency tumors. Virally induced cancer cells all express viral antigens, or molecules that mark them as foreign to the host and make them the targets for the immune attack. For the virally induced tumor cells to continue to replicate, they must be protected from the immune system's attack, so, Golovkina's team searched for a microbe-dependent immune evasion mechanism that enabled virally induced cancer cells to survive in the host. The team performed a series of experiments with immunodeficient mice that were specially engineered, so they lacked the adaptive immune system. In the germ-free setting, these mice developed tumors when exposed to the virus with the same frequency as immunosufficient SPF mice with intact immune systems. So, the anti-tumor immune response was being counteracted by microorganisms, which were subsequently identified as commensal bacteria. The researchers then found that commensal bacteria induced three genes known as negative immune regulators in infected mice. These genes normally act to shut down the immune system after it dealt with a pathogen, but in this case, they held back an immune response directed against cancer cells. Two of the three upregulated negative immune regulators -- Serpinb9b and Rnf128 -- are also known to be indicators of poor prognosis for humans with some spontaneous cancers. Not all commensal bacteria had tumor promoting properties, so Golovkina and her team are continuing to research more on why this immune suppressing capability only comes into play when both virus and bacteria are present. "Now we have to figure out what's so special about bacteria which have these properties," she said. The study, "Gut commensal bacteria enhance pathogenesis of a tumorigenic murine retrovirus," was supported by the National Institutes of Health and National Institute of Diabetes and Digestive and Kidney Diseases Digestive Disease Research Core Center. Additional authors include Jessica Spring, Aly A. Khan, Sophie Lara, Kelly O'Grady, Jessica Wilks, Sandeep Gurbuxani, Steven Erickson, and Alexander Chervonsky from the University of Chicago; and Michael Fischbach and Amy Jacobson from Stanford University.