Peripheral priming induces plastic transcriptomic and proteomic responses in circulating neutrophils required for pathogen containment.

Neutrophils rapidly respond to inflammation and infection, but to which degree their functional trajectories after mobilization from the bone marrow are shaped within the circulation remains vague. Experimental limitations have so far hampered neutrophil research in human disease. Here, using innovative fixation and single-cell-based toolsets, we profile human and murine neutrophil transcriptomes and proteomes during steady state and bacterial infection. We find that peripheral priming of circulating neutrophils leads to dynamic shifts dominated by conserved up-regulation of antimicrobial genes across neutrophil substates, facilitating pathogen containment. We show the TLR4/NF-κB signaling-dependent up-regulation of canonical neutrophil activation markers like CD177/NB-1 during acute inflammation, resulting in functional shifts in vivo. Blocking de novo RNA synthesis in circulating neutrophils abrogates these plastic shifts and prevents the adaptation of antibacterial neutrophil programs by up-regulation of distinct effector molecules upon infection. These data underline transcriptional plasticity as a relevant mechanism of functional neutrophil reprogramming during acute infection to foster bacterial containment within the circulation.

Mural cell-derived chemokines provide a protective niche to safeguard vascular macrophages and limit chronic inflammation.

Maladaptive, non-resolving inflammation contributes to chronic inflammatory diseases such as atherosclerosis. Because macrophages remove necrotic cells, defective macrophage programs can promote chronic inflammation with persistent tissue injury. Here, we investigated the mechanisms sustaining vascular macrophages. Intravital imaging revealed a spatiotemporal macrophage niche across vascular beds alongside mural cells (MCs)-pericytes and smooth muscle cells. Single-cell transcriptomics, co-culture, and genetic deletion experiments revealed MC-derived expression of the chemokines CCL2 and MIF, which actively preserved macrophage survival and their homeostatic functions. In atherosclerosis, this positioned macrophages in viable plaque areas, away from the necrotic core, and maintained a homeostatic macrophage phenotype. Disruption of this MC-macrophage unit via MC-specific deletion of these chemokines triggered detrimental macrophage relocalizing, exacerbated plaque necrosis, inflammation, and atheroprogression. In line, CCL2 inhibition at advanced stages of atherosclerosis showed detrimental effects. This work presents a MC-driven safeguard toward maintaining the homeostatic vascular macrophage niche.

Terrestrial Zen master: Transcriptomics in long-term aestivation and arousal of Mediterranean earthworms.

Earthworms have a crucial role in the maintenance of the biotic and abiotic soil properties, which is important for the biodiversity and productivity of terrestrial ecosystems, especially in the current scenario of climate change. Aestivation is a form of dormancy witnessed in organisms living in deserts or semiarid environments such as the ones found in the central part of the Iberian Peninsula. This work employs next-generation sequencing techniques to explore the changes in gene expression of different aestivation times (1 month and 1 year) as well as changes in gene expression upon arousal. Not surprisingly, the more the aestivation persisted the higher levels of gene downregulation were observed. Conversely, upon arousal, a quick recovery of the levels of gene expression were noted, comparable to the control. Transcriptional changes related to immune responses coming predominantly from abiotic stressors in aestivating earthworms and from biotic stressors in aroused earthworms triggered regulation of the cell fate via apoptosis. Long-term aestivation seemed to be enabled by remodeling of the extracellular matrix, activity of DNA repair mechanisms, and inhibitory neurotransmitters, which could also play a role in lifespan increase. Arousal from 1-month aestivation was on the other hand, characterized by regulation of the cell division cycle. Since aestivation is considered as an unfavorable metabolic state, aroused earthworms probably go through a damage removal process and a subsequent reparation process. This study provides the first transcriptomic investigation done on earthworms in such long aestivation times as well as arousal demonstrating the resilience and adaptability of Carpetania matritensis.