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Metastasis is the leading cause of cancer-related deaths and myeloid cells are critical in the metastatic microenvironment. Here, we explore the implications of reprogramming pre-metastatic niche myeloid cells by inducing trained immunity with whole beta-glucan particle (WGP). WGP-trained macrophages had increased responsiveness not only to lipopolysaccharide but also to tumor-derived factors. WGP in vivo treatment led to a trained immunity phenotype in lung interstitial macrophages, resulting in inhibition of tumor metastasis and survival prolongation in multiple mouse models of metastasis. WGP-induced trained immunity is mediated by the metabolite sphingosine-1-phosphate. Adoptive transfer of WGP-trained bone marrow-derived macrophages reduced tumor lung metastasis. Blockade of sphingosine-1-phosphate synthesis and mitochondrial fission abrogated WGP-induced trained immunity and its inhibition of lung metastases. WGP also induced trained immunity in human monocytes, resulting in antitumor activity. Our study identifies the metabolic sphingolipid–mitochondrial fission pathway for WGP-induced trained immunity and control over metastasis.

Wastewater monitoring has been used to identify SARS-CoV-2 outbreaks and track new variants. This sentinel system should be expanded to monitor other pathogens and boost public health preparedness.

Ethanol (EtOH)-induced alterations in intestinal homeostasis lead to multi-system pathologies, including liver injury. ω-6 PUFAs exert pro-inflammatory activity, while ω-3 PUFAs promote anti-inflammatory activity that is mediated, in part, through specialized pro-resolving mediators [e.g., resolvin D1 (RvD1)]. We tested the hypothesis that a decrease in the ω-6:ω-3 PUFA ratio would attenuate EtOH-mediated alterations in the gut-liver axis. ω-3 FA desaturase-1 (fat-1) mice, which endogenously increase ω-3 PUFA levels, were protected against EtOH-mediated downregulation of intestinal tight junction proteins in organoid cultures and in vivo. EtOH- and lipopolysaccharide-induced expression of INF-γ, Il-6, and Cxcl1was attenuated in fat-1and WT RvD1-treated mice. RNA-seq of ileum tissue revealed upregulation of several genes involved in cell proliferation, stem cell renewal, and antimicrobial defense (including Alpiand Leap2) in fat-1versus WT mice fed EtOH. fat-1mice were also resistant to EtOH-mediated downregulation of genes important for xenobiotic/bile acid detoxification. Further, gut microbiome and plasma metabolomics revealed several changes in fat-1versus WT mice that may contribute to a reduced inflammatory response. Finally, these data correlated with a significant reduction in liver injury. Our study suggests that ω-3 PUFA enrichment or treatment with resolvins can attenuate the disruption in intestinal homeostasis caused by EtOH consumption and systemic inflammation with a concomitant reduction in liver injury.

Background: Despite a clear appreciation of the impact of human pathogens on community health, efforts to understand pathogen dynamics within populations often follow a narrow-targeted approach and rely on the deployment of specific molecular probes for quantitative detection or rely on clinical detection and reporting. Main text: Genomic analysis of wastewater samples for the broad detection of viruses, bacteria, fungi, and antibiotic resistance genes of interest/concern is inherently difficult, and while deep sequencing of wastewater provides a wealth of information, a robust and cooperative foundation is needed to support healthier communities. In addition to furthering the capacity of high-throughput sequencing wastewater-based epidemiology to detect human pathogens in an unbiased and agnostic manner, it is critical that collaborative networks among public health agencies, researchers, and community stakeholders be fostered to prepare communities for future public health emergencies or for the next pandemic. A more inclusive public health infrastructure must be built for better data reporting where there is a global human health risk burden. Conclusions: As wastewater platforms continue to be developed and refined, high-throughput sequencing of human pathogens in wastewater samples will emerge as a gold standard for understanding community health.

The IL-1 signaling pathway has been shown to play a critical role in the pathogenesis of chronic, autoinflammatory skin diseases such as psoriasis. However, the exact cellular and molecular mechanisms have not been fully understood. Here, we show that IL-1β is significantly elevated in psoriatic lesional skin and imiquimod-treated mouse skin. In addition, IL-1R signaling appears to correlate with psoriasis disease progression and treatment response. IL-1 signaling in both dermal γδ T cells and other cells such as keratinocytes is essential to an IMQ-induced skin inflammation. IL-1β induces dermal γδ T cell proliferation and IL-17 production in mice. In addition, IL-1β stimulates keratinocytes to secrete chemokines that preferentially chemoattract peripheral CD27–CCR6+IL-17 capable of producing γδ T cells (γδT17). Further studies showed that endogenous IL-1β secretion is regulated by skin commensals to maintain dermal γδT17 homeostasis in mice. Mouse skin associated with Corynebacteriumspecies, bacteria enriched in human psoriatic lesional skin, has increased IL-1β and dermal γδT17 cell expansion. Thus, the IL-1β–IL-1R signaling pathway may contribute to skin inflammation and psoriasis pathogenesis via the direct regulation of dermal IL-17–producing cells and stimulation of keratinocytes for amplifying inflammatory cascade.

Astronauts participating in long duration space missions are likely to be exposed to ionizing radiation associated with highly energetic and charged heavy particles. Previously proposed gene biomarkers for radiation exposure include phosphorylated H2A Histone Family, Member X (γH2AX), Tumor Protein 53 (TP53), and Cyclin-Dependent Kinase Inhibitor 1A (CDKN1A). However, transcripts of these genes may not be the most suitable biomarkers for radiation exposure due to a lack of sensitivity or specificity. As part of a larger effort to develop lab-on-a-chip methods for detecting radiation exposure events using blood samples, we designed a dose–course microarray study in order to determine coding and non-coding RNA transcripts undergoing differential expression immediately following radiation exposure. The main goal was to elicit a small set of sensitive and specific radiation exposure biomarkers at low, medium, and high levels of ionizing radiation exposure. Four separate levels of radiation were considered: 0Gray (Gy) control; 0.3Gy; 1.5Gy; and 3.0Gy with four replicates at each radiation level. This report includes raw gene expression data files from the resulting microarray experiments from all three radiation levels ranging from a lower, typical exposure than an astronaut might see (0.3Gy) to high, potentially lethal, levels of radiation (3.0Gy). The data described here is available in NCBI's Gene Expression Omnibus (GEO), accession GSE64375.

Fats are essential in healthy diets, but how dietary fats affect immune cell function and overall health is not well understood. Mimicking human high-fat diets (HFDs), which are rich in different fatty acid (FA) components, we fed mice various HFDs from different fat sources, including fish oil and cocoa butter. Mice consuming the fish oil HFD exhibit a hair-loss phenotype. Further studies show that omega-3 (n-3) FAs in fish oil promote atypical infiltration of CD207−(langerin−) myeloid macrophages in skin dermis, which induce hair loss through elevated TNF-α signaling. Mechanistically, epidermal fatty acid binding protein (E-FABP) is demonstrated to play an essential role in inducing TNF-α-mediated hair loss by activating the n-3 FA/ROS/IL-36 signaling pathway in dermal resident macrophages. Absence of E-FABP abrogates fish oil HFD-induced murine hair loss. Altogether, these findings support a role for E-FABP as a lipid sensor mediating n-3 FA-regulated macrophage function and skin health.

Primary afferent collateral sprouting is a process whereby non-injured primary afferent neurons respond to some stimulus and extend new branches from existing axons. Neurons of both the central and peripheral nervous systems undergo this process, which contributes to both adaptive and maladaptive plasticity (e.g., [1–9]). In the model used here (the “spared dermatome” model), the intact sensory neurons respond to the denervation of adjacent areas of skin by sprouting new axon branches into that adjacent denervated territory. Investigations of gene expression changes associated with collateral sprouting can provide a better understanding of the molecular mechanisms controlling this process. Consequently, it can be used to develop treatments to promote functional recovery for spinal cord injury and other similar conditions. This report includes raw gene expression data files from microarray experiments in order to study the gene regulation in spared sensory ganglia in the initiation (7days) and maintenance (14days) phases of the spared dermatome model relative to intact (“naïve”) sensory ganglia. Data has been deposited into GEO (GSE72551).

ABSTRACTYersinia pestishas evolved many strategies to evade the innate immune system. One of these strategies is the ability to survive within macrophages. Upon phagocytosis, Y. pestisprevents phagolysosome maturation and establishes a modified compartment termed the Yersinia-containing vacuole (YCV). Y. pestisactively inhibits the acidification of this compartment, and eventually, the YCV transitions from a tight-fitting vacuole into a spacious replicative vacuole. The mechanisms to generate the YCV have not been defined. However, we hypothesized that YCV biogenesis requires Y. pestisinteractions with specific host factors to subvert normal vesicular trafficking. In order to identify these factors, we performed a genome-wide RNA interference (RNAi) screen to identify host factors required for Y. pestissurvival in macrophages. This screen revealed that 71 host proteins are required for intracellular survival of Y. pestis. Of particular interest was the enrichment for genes involved in endosome recycling. Moreover, we demonstrated that Y. pestisactively recruits Rab4a and Rab11b to the YCV in a type three secretion system-independent manner, indicating remodeling of the YCV by Y. pestisto resemble a recycling endosome. While recruitment of Rab4a was necessary to inhibit YCV acidification and lysosomal fusion early during infection, Rab11b appeared to contribute to later stages of YCV biogenesis. We also discovered that Y. pestisdisrupts global host endocytic recycling in macrophages, possibly through sequestration of Rab11b, and this process is required for bacterial replication. These data provide the first evidence that Y. pestistargets the host endocytic recycling pathway to avoid phagolysosomal maturation and generate the YCV.IMPORTANCEYersinia pestiscan infect and survive within macrophages. However, the mechanisms that the bacterium use to subvert killing by these phagocytes have not been defined. To provide a better understanding of these mechanisms, we used an RNAi approach to identify host factors required for intracellular Y. pestissurvival. This approach revealed that the host endocytic recycling pathway is essential for Y. pestisto avoid clearance by the macrophage. We further demonstrate that Y. pestisremodels the phagosome to resemble a recycling endosome, allowing the bacterium to avoid the normal phagolysosomal maturation pathway. Moreover, we show that infection with Y. pestisdisrupts normal recycling in the macrophage and that disruption is required for bacterial replication. These findings provide the first evidence that Y. pestistargets the host endocytic recycling pathway in order to evade killing by macrophages.

ABSTRACTInflammation and infection are key promoters of colon cancer but the molecular interplay between these events is largely unknown. Mice deficient in leukotriene B4receptor1 (BLT1) are protected in inflammatory disease models of arthritis, asthma and atherosclerosis. In this study, we show that BLT1−/−mice when bred onto a spontaneous tumor (ApcMin/+) model displayed an increase in the rate of intestinal tumor development and mortality. A paradoxical increase in inflammation in the tumors from the BLT1−/−ApcMin/+mice is coincidental with defective host response to infection. Germ-free BLT1−/−ApcMin/+mice are free from colon tumors that reappeared upon fecal transplantation. Analysis of microbiota showed defective host response in BLT1−/−ApcMin/+mice reshapes the gut microbiota to promote colon tumor development. The BLT1−/−MyD88−/−double deficient mice are susceptible to lethal neonatal infections. Broad-spectrum antibiotic treatment eliminated neonatal lethality in BLT1−/−MyD88−/−mice and the BLT1−/−MyD88−/−ApcMin+mice are protected from colon tumor development. These results identify a novel interplay between the Toll-like receptor mediated microbial sensing mechanisms and BLT1-mediated host response in the control of colon tumor development.