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The study of human macrophages and their ontogeny is an important unresolved issue. Here, we use a humanized mouse model expressing human cytokines to dissect the development of lung macrophages from human hematopoiesis in vivo. Human CD34+ hematopoietic stem and progenitor cells (HSPCs) generated three macrophage populations, occupying separate anatomical niches in the lung. Intravascular cell labeling, cell transplantation, and fate-mapping studies established that classical CD14+ blood monocytes derived from HSPCs migrated into lung tissue and gave rise to human interstitial and alveolar macrophages. In contrast, non-classical CD16+ blood monocytes preferentially generated macrophages resident in the lung vasculature (pulmonary intravascular macrophages). Finally, single-cell RNA sequencing defined intermediate differentiation stages in human lung macrophage development from blood monocytes. This study identifies distinct developmental pathways from circulating monocytes to lung macrophages and reveals how cellular origin contributes to human macrophage identity, diversity, and localization in vivo.Geoffrey Burnstock, one of the most talented and brilliant scientists of his generation, was born on the 10th of May 1929 in London and died on the 2ndof June 2020, aged 91, in Melbourne (Australia). Geoffrey Burnstock started his research studies with an interest in the nerves controlling the guts of guinea pigs, and discovered a completely unexpected and ubiquitous signalling system mediated via extracellular nucleotides (the "purinergic theory"), which revolutionized our understanding of how cells communicate between each other. He made the highly controversial discovery that ATP (adenosine triphosphate), a molecule well known to biochemists for its role as a source of energy inside cells, could also transmit signals between them. Initially, his somewhat heretical theory, that did not fit conventional views, found considerable resistance in the scientific community. However, he continued to accumulate evidence in favor of his hypothesis, extending it to a variety of organs and systems and demonstrating a ruman being, always eager to collaborate and share data, never jealous of his findings and capable of learning even from young people. He was known for his enthusiasm, empathy and ability to motivate young scientists. I was lucky to meet him when I was still very young, and the collaboration and friendship that we established and maintained across the years has profoundly conditioned my professional and personal life. For me, Geoff was what in Italy we call a "Maestro", one of those leading figures who are fundamental not only for mentoring an individual's career but also their growth as a scientist and as a human being.Fundamental progresses have been made in pain research with a comprehensive understanding of the neuronal pathways which convey painful sensations from the periphery and viscera to the central nervous system and of the descending modulating pathways. Nevertheless, many patients still suffer from various painful conditions, which are often associated to other primary pathologies, and get no or poor relief from available painkillers. Thus, the interest of many researchers has concentrated on new and promising cellular targets and biochemical pathways. This is the case of glia cells, both in the peripheral and in the central nervous system, and of purinergic receptors. Starting from many intuitions and hypotheses raised by Prof. Geoffrey Burnstock, data have accumulated which clearly highlight the fundamental role exerted by several nucleotide and nucleoside receptors in the modulation of glial cell reaction to pain triggers and of their cross-talk with sensory neurons which significantly contributes to the transition from acute to chronic pain. The purinergic system has therefore become an appealing pharmacological target in pain research, also based on the quite unexpected discovery that purines are involved in ancient analgesic techniques such as acupuncture. SAR131675 molecular weight A more in-depth understanding of the complex and intricated purine-orchestrated scenario in pain conditions will hopefully lead to the identification and clinical development of new and effective analgesics.Dedicator of cytokinesis 2 (DOCK2), an atypical Rac activator, has important anti-inflammatory properties in blepharitis, enteric bacterial infection and colitis. However, the roles of DOCK2 in macrophage activation and acute lung injury (ALI) are still poorly elucidated. In vitro studies demonstrated that DOCK2 was essential for the nucleotide-sensing Toll-like receptor (TLR) 4-mediated inflammatory response in macrophages. We also confirmed that exposure of macrophages to LPS induced Rac activation through a TLR4-independent, DOCK2-dependent mechanism. Phosphorylation of IκB kinase (IKK) β and nuclear translocation of transcription factor nuclear factor kappa B (NF-κB) were impaired in Ad-shDOCK2-expressing macrophages, resulting in a decreased inflammatory response. Similar results were obtained when EHop-016 (a Rac inhibitor) was used to treat uninfected macrophages. In summary, these data indicate that the DOCK2-Rac signaling pathway acts in parallel with TLR4 engagement to control IKKβ activation for inflammatory cytokine release. Next, we investigated whether pharmacological inhibition of DOCK2 protects against endotoxemia-induced lung injury in mice. Treatment with 4-[3'-(2″-chlorophenyl)-2'-propen-1'-ylidene]-1-phenyl-3,5-pyrazolidinedione (CPYPP), a small-molecule inhibitor of DOCK2, reduced the severity of lung injury, as indicated by decreases in the lung injury score and myeloperoxidase (MPO) activity. Moreover, CPYPP attenuated LPS-induced proinflammatory cytokine release in mice. Our studies suggest that inhibition of DOCK2 may suppress LPS-induced macrophage activation and that DOCK2 may be a novel target for treating endotoxemia-related ALI.The coronavirus disease 2019 (COVID-19) pandemic has claimed the lives of over one million people worldwide. The causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a member of the Coronaviridae family of viruses that can cause respiratory infections of varying severity. The cellular host factors and pathways co-opted during SARS-CoV-2 and related coronavirus life cycles remain ill defined. To address this gap, we performed genome-scale CRISPR knockout screens during infection by SARS-CoV-2 and three seasonal coronaviruses (HCoV-OC43, HCoV-NL63, and HCoV-229E). These screens uncovered host factors and pathways with pan-coronavirus and virus-specific functional roles, including major dependency on glycosaminoglycan biosynthesis, sterol regulatory element-binding protein (SREBP) signaling, bone morphogenetic protein (BMP) signaling, and glycosylphosphatidylinositol biosynthesis, as well as a requirement for several poorly characterized proteins. We identified an absolute requirement for the VMP1, TMEM41, and TMEM64 (VTT) domain-containing protein transmembrane protein 41B (TMEM41B) for infection by SARS-CoV-2 and three seasonal coronaviruses.
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