IRGM promotes glioma M2 macrophage polarization through p62/TRAF6/NF-κB pathway mediated IL-8 production. Xu Yanwen,Liao Chuanpeng,Liu Renli,Liu Jing,Chen Zhongping,Zhao Huafu,Li Zongyang,Chen Lei,Wu Changpeng,Tan Hui,Liu Wenlan,Li Weiping Cell biology international Alternatively activated (M2) macrophage promotes glioma progression and immune escape as the most immunocyte in glioma microenvironment. Finding out the key protein regulating M2 macrophage polarization is necessary for improving treatment. Whether immunity related GTPase M (IRGM) is involved in glioma development and M2 macrophage polarization is unknown. IRGM and M2 macrophage marker CD206 expression were examined using immunohistochemistry among 35 glioma and 11 non-cancerous brain specimens. We found IRGM scores were positively correlated with CD206 scores in glioma specimens and monocyte proportion in blood samples. A172 glioma cells transfected with either IRGM knock-down lentivirus (Lenti-IRGM) or control lentivirus (Lenti-HK) were subcutaneously injected into nude mice. In vivo, xenografted glioma size of the Lenti-IRGM group was smaller and had weaker fluorescence signal than Lenti-HK control group. Immunofluorescence results showed that there was obviously decreased IRGM, CD206, and IL-8 expression in the mice glioma of Lenti-IRGM group than Lenti-HK control group. In vitro, flow cytometry results showed that M2 polarization from THP-1 cocultured with Lenti-IRGM glioma cells decreased in contrast to that with Lenti-HK glioma cells; there were less interleukin-8 (IL-8) and macrophage inflammation protein 3-α (MIP-3α), but more interleukin-6 (IL-6) in the supernatant of Lenti-IRGM glioma cells than matched control. Western blot and immunofluorescence displayed that IRGM strongly promoted sequestosome-1 (p62/SQSTM1), necrosis factor receptor-activating factor 6 (TRAF6) expression and NF-κB transportation to the nucleus. Realtime PCR results demonstrated IRGM also promoted NF-κB downstream cytokines IL-8 and MIP-3α mRNA expression. These data suggested that IRGM could promote glioma development and M2 macrophage polarization by regulating p62/TRAF6/NF-κB pathway-mediated IL-8 production. 10.1002/cbin.11061

NF-κB signaling pathway in tumor microenvironment. Frontiers in immunology The genesis and progression of tumors are multifaceted processes influenced by genetic mutations within the tumor cells and the dynamic interplay with their surrounding milieu, which incessantly impacts the course of cancer. The tumor microenvironment (TME) is a complex and dynamic entity that encompasses not only the tumor cells but also an array of non-cancerous cells, signaling molecules, and the extracellular matrix. This intricate network is crucial in tumor progression, metastasis, and response to treatments. The TME is populated by diverse cell types, including immune cells, fibroblasts, endothelial cells, alongside cytokines and growth factors, all of which play roles in either suppressing or fostering tumor growth. Grasping the nuances of the interactions within the TME is vital for the advancement of targeted cancer therapies. Consequently, a thorough understanding of the alterations of TME and the identification of upstream regulatory targets have emerged as a research priority. NF-κB transcription factors, central to inflammation and innate immunity, are increasingly recognized for their significant role in cancer onset and progression. This review emphasizes the crucial influence of the NF-κB signaling pathway within the TME, underscoring its roles in the development and advancement of cancer. By examining the interactions between NF-κB and various components of the TME, targeting the NF-κB pathway appears as a promising cancer treatment approach. 10.3389/fimmu.2024.1476030

NF-κB: Governing Macrophages in Cancer. Genes Tumor-associated macrophages (TAMs) are the major component of the tumor microenvironment (TME), where they sustain tumor progression and or-tumor immunity. Due to their plasticity, macrophages can exhibit anti- or pro-tumor functions through the expression of different gene sets leading to distinct macrophage phenotypes: M1-like or pro-inflammatory and M2-like or anti-inflammatory. NF-κB transcription factors are central regulators of TAMs in cancers, where they often drive macrophage polarization toward an M2-like phenotype. Therefore, the NF-κB pathway is an attractive therapeutic target for cancer immunotherapy in a wide range of human tumors. Hence, targeting NF-κB pathway in the myeloid compartment is a potential clinical strategy to overcome microenvironment-induced immunosuppression and increase anti-tumor immunity. In this review, we discuss the role of NF-κB as a key driver of macrophage functions in tumors as well as the principal strategies to overcome tumor immunosuppression by targeting the NF-κB pathway. 10.3390/genes15020197