A PRMT5-ZNF326 axis mediates innate immune activation upon replication stress.

DNA replication stress (RS) is a widespread phenomenon in carcinogenesis, causing genomic instability and extensive chromatin alterations. DNA damage leads to activation of innate immune signaling, but little is known about transcriptional regulators mediating such signaling upon RS. Using a chemical screen, we identified protein arginine methyltransferase 5 (PRMT5) as a key mediator of RS-dependent induction of interferon-stimulated genes (ISGs). This response is also associated with reactivation of endogenous retroviruses (ERVs). Using quantitative mass spectrometry, we identify proteins with PRMT5-dependent symmetric dimethylarginine (SDMA) modification induced upon RS. Among these, we show that PRMT5 targets and modulates the activity of ZNF326, a zinc finger protein essential for ISG response. Our data demonstrate a role for PRMT5-mediated SDMA in the context of RS-induced transcriptional induction, affecting physiological homeostasis and cancer therapy.

Spatially-resolved transcriptomics reveal macrophage heterogeneity and prognostic significance in diffuse large B-cell lymphoma.

Macrophages are abundant immune cells in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Macrophage estimation by immunohistochemistry shows varying prognostic significance across studies in DLBCL, and does not provide a comprehensive analysis of macrophage subtypes. Here, using digital spatial profiling with whole transcriptome analysis of CD68+ cells, we characterize macrophages in distinct spatial niches of reactive lymphoid tissues (RLTs) and DLBCL. We reveal transcriptomic differences between macrophages within RLTs (light zone /dark zone, germinal center/ interfollicular), and between disease states (RLTs/ DLBCL), which we then use to generate six spatially-derived macrophage signatures (MacroSigs). We proceed to interrogate these MacroSigs in macrophage and DLBCL single-cell RNA-sequencing datasets, and in gene-expression data from multiple DLBCL cohorts. We show that specific MacroSigs are associated with cell-of-origin subtypes and overall survival in DLBCL. This study provides a spatially-resolved whole-transcriptome atlas of macrophages in reactive and malignant lymphoid tissues, showing biological and clinical significance.

Rift Valley Fever Virus Primes Immune Responses in Aedes aegypti Cells.

The ongoing global emergence of arthropod-borne (arbo) viruses has accelerated research into the interactions of these viruses with the immune systems of their vectors. Only limited information exists on how bunyaviruses, such as Rift Valley fever virus (RVFV), are sensed by mosquito immunity or escape detection. RVFV is a zoonotic phlebovirus (Bunyavirales; Phenuiviridae) of veterinary and human public health and economic importance. We have shown that the infection of mosquitoes with RVFV triggers the activation of RNA interference pathways, which moderately restrict viral replication. Here, we aimed to better understand the interactions between RVFV and other vector immune signaling pathways that might influence RVFV replication and transmission. For this, we used the immunocompetent Aedes aegypti Aag2 cell line as a model. We found that bacteria-induced immune responses restricted RVFV replication. However, virus infection alone did not alter the gene expression levels of immune effectors. Instead, it resulted in the marked enhancement of immune responses to subsequent bacterial stimulation. The gene expression levels of several mosquito immune pattern recognition receptors were altered by RVFV infection, which may contribute to this immune priming. Our findings imply that there is a complex interplay between RVFV and mosquito immunity that could be targeted in disease prevention strategies.

Radiation-induced neuropathological changes in the oligodendrocyte lineage with relevant clinical manifestations and therapeutic strategies.

PURPOSE: With technological advancements in radiation therapy for tumors of the central nervous system (CNS), high doses of ionizing radiation can be delivered to the tumors with improved accuracy. Despite the reduction of ionizing radiation-induced toxicity to surrounding tissues of the CNS, a wide array of side effects still occurs, particularly late-delayed changes. These alterations, such as white matter damages and neurocognitive impairments, are often debilitative and untreatable, significantly affecting the quality of life of these patients, especially children. Oligodendrocytes, a major class of glial cells, have been identified to be one of the targets of radiation toxicity and are recognized be involved in late-delayed radiation-induced neuropathological changes. These cells are responsible for forming the myelin sheaths that surround and insulate axons within the CNS. Here, the effects of ionizing radiation on the oligodendrocyte lineage as well as the common clinical manifestations resulting from radiation-induced damage to oligodendrocytes will be discussed. Potential prophylactic and therapeutic strategies against radiation-induced oligodendrocyte damage will also be considered. CONCLUSION: Oligodendrocytes and oligodendrocyte progenitor cells (OPCs) are radiosensitive cells of the CNS. Here, general responses of these cells to radiation exposure have been outlined. However, several findings have not been consistent across various studies. For instance, cognitive decline in irradiated animals was observed to be accompanied by obvious demyelination or white matter changes in several studies but not in others. Hence, further studies have to be conducted to elucidate the level of contribution of the oligodendrocyte lineage to the development of late-delayed effects of radiation exposure, as well as to classify the dose and brain region-specific responses of the oligodendrocyte lineage to radiation. Several potential therapeutic approaches against late-delayed changes have been discussed, such as the transplantation of OPCs into irradiated regions and implementation of exercise. Many of these approaches show promising results. Further elucidation of the mechanisms involved in radiation-induced death of oligodendrocytes and OPCs would certainly aid in the development of novel protective and therapeutic strategies against the late-delayed effects of radiation.

Ionizing Radiation-Induced Brain Cell Aging and the Potential Underlying Molecular Mechanisms.

Population aging is occurring rapidly worldwide, challenging the global economy and healthcare services. Brain aging is a significant contributor to various age-related neurological and neuropsychological disorders, including Alzheimer's disease and Parkinson's disease. Several extrinsic factors, such as exposure to ionizing radiation, can accelerate senescence. Multiple human and animal studies have reported that exposure to ionizing radiation can have varied effects on organ aging and lead to the prolongation or shortening of life span depending on the radiation dose or dose rate. This paper reviews the effects of radiation on the aging of different types of brain cells, including neurons, microglia, astrocytes, and cerebral endothelial cells. Further, the relevant molecular mechanisms are discussed. Overall, this review highlights how radiation-induced senescence in different cell types may lead to brain aging, which could result in the development of various neurological and neuropsychological disorders. Therefore, treatment targeting radiation-induced oxidative stress and neuroinflammation may prevent radiation-induced brain aging and the neurological and neuropsychological disorders it may cause.