Rat leukocyte population dynamics predicts a window for intervention in aging.

Age-associated changes in human hematopoiesis have been mostly recapitulated in mouse models; but not much has been explored in rats, a physiologically closer model to humans. To establish whether rat hematopoiesis closely mirrors humans’, we examined the peripheral blood of rats throughout their lifespan. Significant age-associated changes showed distinctive population shifts predictive of age. A divergence between predicted versus chronological age changes was indicative of fragility; thus, these data may be a valuable tool to identify underlying diseases or as a surrogate predictor for intervention efficacy. Notably, several blood parameters and DNA methylation alterations defined specific leverage points during aging, supporting non-linear aging effects and highlighting a roadmap for interventions at these junctures. Overall, we present a simple set of rat blood metrics that can provide a window into their health and inform the implementation of interventions in a model system physiologically relevant for humans.

ScRNA-Seq study of neutrophils reveals vast heterogeneity and breadth of inflammatory responses in severe COVID-19 patients

Severe cases of COVID-19 are characterized by dysregulated immune responses, but specific mechanisms contributing to the most severe outcomes remain unclear. Neutrophils are the most abundant leukocyte population in human hosts and reach markedly high numbers during severe COVID-19. However, a detailed examination of their responses has been largely overlooked in the COVID-19 literature to date. Here, we report for the first time a dedicated study of neutrophil responses using single-cell RNA sequencing (scRNA-Seq) of fresh leukocytes from 11 hospitalized adult patients with mild and severe COVID-19 disease and 5 healthy controls. We observed that neutrophils display a pronounced inflammatory profile, with dramatic disruption of predicted cell-cell interactions as the severity of the disease increases. We also identified unique mature and immature neutrophil subpopulations based on transcriptomic profiling, including an antiviral phenotype, and changes in the proportion of each population linked to the severity of the disease. Finally, pathway analysis revealed increased markers of oxidative phosphorylation and ribosomal genes, along with downregulation of many antiviral and host defense pathway genes during severe disease compared to mild infections. Collectively, our findings indicate that neutrophils are capable of mounting effective antiviral defenses but adopt a form of immune dysregulation characterized by excess cellular stress, thereby contributing to the pathogenesis of severe COVID-19.

Polystyrene microplastic particles induce endothelial activation

Due to its increasing production, durability and multiple applications, plastic is a material we encounter every day. Small plastic particles from the μm to the mm range are classified as microplastics and produced for cosmetic and medical products, but are also a result of natural erosion and decomposition of macroplastics. Although being omnipresent in our environment and already detected in various organisms, less is known about the effects of microplastics on humans in general, or on vascular biology in particular. Here we investigated the effects of carboxylated polystyrene microplastic particles (PS, 1 μm) on murine endothelial and immune cells, which are both crucially involved in vascular inflammation, using in vitro and in vivo approaches. In vitro, PS induced adhesion molecule expression in endothelial cells with subsequent adhesion of leukocytes both under static and flow conditions. In monocytic cells, PS enhanced pro-inflammatory cytokine expression and release. Accordingly, administering mice with PS led to enhanced aortic expression of cytokines and adhesion molecules. Furthermore, we identified neutrophils as the PS-clearing blood leukocyte population. The findings from this study for the first time indicate polystyrene microplastic as a new environmental risk factor for endothelial inflammation.

Targeting Tumor-Associated Macrophages in Cancer Immunotherapy

Tumor-associated macrophages (TAMs) represent the most abundant leukocyte population in most solid tumors and are greatly influenced by the tumor microenvironment. More importantly, these macrophages can promote tumor growth and metastasis through interactions with other cell populations within the tumor milieu and have been associated with poor outcomes in multiple tumors. In this review, we examine how the tumor microenvironment facilitates the polarization of TAMs. Additionally, we evaluate the mechanisms by which TAMs promote tumor angiogenesis, induce tumor invasion and metastasis, enhance chemotherapeutic resistance, and foster immune evasion. Lastly, we focus on therapeutic strategies that target TAMs in the treatments of cancer, including reducing monocyte recruitment, depleting or reprogramming TAMs, and targeting inhibitory molecules to increase TAM-mediated phagocytosis.

Current Understanding of the Neutrophil Transcriptome in Health and Disease

Neutrophils are key cells of the innate immune system. It is now understood that this leukocyte population is diverse in both the basal composition and functional plasticity. Underlying this plasticity is a post-translational framework for rapidly achieving early activation states, but also a transcriptional capacity that is becoming increasingly recognized by immunologists. Growing interest in the contribution of neutrophils to health and disease has resulted in more efforts to describe their transcriptional activity. Whilst initial efforts focused predominantly on understanding the existing biology, investigations with advanced methods such as single cell RNA sequencing to understand interactions of the entire immune system are revealing higher flexibility in neutrophil transcription than previously thought possible and multiple transition states. It is now apparent that neutrophils utilise many forms of RNA in the regulation of their function. This review collates current knowledge on the nuclei structure and gene expression activity of human neutrophils across homeostasis and disease, before highlighting knowledge gaps that are research priority areas.