Co-option of Neutrophil Fates by Tissue Environments.

Classically considered short-lived and purely defensive leukocytes, neutrophils are unique in their fast and moldable response to stimulation. This plastic behavior may underlie variable and even antagonistic functions during inflammation or cancer, yet the full spectrum of neutrophil properties as they enter healthy tissues remains unexplored. Using a new model to track neutrophil fates, we found short but variable lifetimes across multiple tissues. Through analysis of the receptor, transcriptional, and chromatin accessibility landscapes, we identify varying neutrophil states and assign non-canonical functions, including vascular repair and hematopoietic homeostasis. Accordingly, depletion of neutrophils compromised angiogenesis during early age, genotoxic injury, and viral infection, and impaired hematopoietic recovery after irradiation. Neutrophils acquired these properties in target tissues, a process that, in the lungs, occurred in CXCL12-rich areas and relied on CXCR4. Our results reveal that tissues co-opt neutrophils en route for elimination to induce programs that support their physiological demands.

A Network of Macrophages Supports Mitochondrial Homeostasis in the Heart.

Cardiomyocytes are subjected to the intense mechanical stress and metabolic demands of the beating heart. It is unclear whether these cells, which are long-lived and rarely renew, manage to preserve homeostasis on their own. While analyzing macrophages lodged within the healthy myocardium, we discovered that they actively took up material, including mitochondria, derived from cardiomyocytes. Cardiomyocytes ejected dysfunctional mitochondria and other cargo in dedicated membranous particles reminiscent of neural exophers, through a process driven by the cardiomyocyte's autophagy machinery that was enhanced during cardiac stress. Depletion of cardiac macrophages or deficiency in the phagocytic receptor Mertk resulted in defective elimination of mitochondria from the myocardial tissue, activation of the inflammasome, impaired autophagy, accumulation of anomalous mitochondria in cardiomyocytes, metabolic alterations, and ventricular dysfunction. Thus, we identify an immune-parenchymal pair in the murine heart that enables transfer of unfit material to preserve metabolic stability and organ function. VIDEO ABSTRACT.

Sublethal necroptosis signaling promotes inflammation and liver cancer.

It is currently not well known how necroptosis and necroptosis responses manifest in vivo. Here, we uncovered a molecular switch facilitating reprogramming between two alternative modes of necroptosis signaling in hepatocytes, fundamentally affecting immune responses and hepatocarcinogenesis. Concomitant necrosome and NF-κB activation in hepatocytes, which physiologically express low concentrations of receptor-interacting kinase 3 (RIPK3), did not lead to immediate cell death but forced them into a prolonged "sublethal" state with leaky membranes, functioning as secretory cells that released specific chemokines including CCL20 and MCP-1. This triggered hepatic cell proliferation as well as activation of procarcinogenic monocyte-derived macrophage cell clusters, contributing to hepatocarcinogenesis. In contrast, necrosome activation in hepatocytes with inactive NF-κB-signaling caused an accelerated execution of necroptosis, limiting alarmin release, and thereby preventing inflammation and hepatocarcinogenesis. Consistently, intratumoral NF-κB-necroptosis signatures were associated with poor prognosis in human hepatocarcinogenesis. Therefore, pharmacological reprogramming between these distinct forms of necroptosis may represent a promising strategy against hepatocellular carcinoma.

Neutrophils in Homeostasis, Immunity, and Cancer.

Neutrophils were among the first leukocytes described and visualized by early immunologists. Prominent effector functions during infection and sterile inflammation classically placed them low in the immune tree as rapid, mindless aggressors with poor regulatory functions. This view is currently under reassessment as we uncover new aspects of their life cycle and identify transcriptional and phenotypic diversity that endows them with regulatory properties that extend beyond their lifetime in the circulation. These properties are revealing unanticipated roles for neutrophils in supporting homeostasis, as well as complex disease states such as cancer. We focus this review on these emerging functions in order to define the true roles of neutrophils in homeostasis, immunity, and disease.

Evolution of the flat band and the role of lattice relaxations in twisted bilayer graphene.

Magic-angle twisted bilayer graphene exhibits correlated phenomena such as superconductivity and Mott insulating states related to the weakly dispersing flat band near the Fermi energy. Such a flat band is expected to be sensitive to both the moiré period and lattice relaxations. Thus, clarifying the evolution of the electronic structure with the twist angle is critical for understanding the physics of magic-angle twisted bilayer graphene. Here we combine nano-spot angle-resolved photoemission spectroscopy and atomic force microscopy to resolve the fine electronic structure of the flat band and remote bands, as well as their evolution with twist angle from 1.07° to 2.60°. Near the magic angle, the dispersion is characterized by a flat band near the Fermi energy with a strongly reduced band width. Moreover, we observe a spectral weight transfer between remote bands at higher binding energy, which allows to extract the modulated interlayer spacing near the magic angle. Our work provides direct spectroscopic information on flat band physics and highlights the important role of lattice relaxations.

Locally renewing resident synovial macrophages provide a protective barrier for the joint.

Macrophages are considered to contribute to chronic inflammatory diseases such as rheumatoid arthritis1. However, both the exact origin and the role of macrophages in inflammatory joint disease remain unclear. Here we use fate-mapping approaches in conjunction with three-dimensional light-sheet fluorescence microscopy and single-cell RNA sequencing to perform a comprehensive spatiotemporal analysis of the composition, origin and differentiation of subsets of macrophages within healthy and inflamed joints, and study the roles of these macrophages during arthritis. We find that dynamic membrane-like structures, consisting of a distinct population of CX3CR1+ tissue-resident macrophages, form an internal immunological barrier at the synovial lining and physically seclude the joint. These barrier-forming macrophages display features that are otherwise typical of epithelial cells, and maintain their numbers through a pool of locally proliferating CX3CR1- mononuclear cells that are embedded into the synovial tissue. Unlike recruited monocyte-derived macrophages, which actively contribute to joint inflammation, these epithelial-like CX3CR1+ lining macrophages restrict the inflammatory reaction by providing a tight-junction-mediated shield for intra-articular structures. Our data reveal an unexpected functional diversification among synovial macrophages and have important implications for the general role of macrophages in health and disease.

Unconventional Spectral Gaps Induced by Charge Density Waves in the Weyl Semimetal (TaSe4)2I.

Coupling Weyl quasiparticles and charge density waves (CDWs) can lead to fascinating band renormalization and many-body effects beyond band folding and Peierls gaps. For the quasi-one-dimensional chiral compound (TaSe4)2I with an incommensurate CDW transition at TC = 263 K, photoemission mappings thus far are intriguing due to suppressed emission near the Fermi level. Models for this unconventional behavior include axion insulator phases, correlation pseudogaps, polaron subbands, bipolaron bound states, etc. Our photoemission measurements show sharp quasiparticle bands crossing the Fermi level at T > TC, but for T < TC, these bands retain their dispersions with no Peierls or axion gaps at the Weyl points. Instead, occupied band edges recede from the Fermi level, opening a spectral gap. Our results confirm localization of quasiparticles (holes created by photoemission) is the key physics, which suppresses spectral weights over an energy window governed by incommensurate modulation and inherent phase defects of CDW.

Macrophages, Metabolism and Heterophagy in the Heart.

The heart is a never-stopping engine that relies on a formidable pool of mitochondria to generate energy and propel pumping. Because dying cardiomyocytes cannot be replaced, this high metabolic rate creates the challenge of preserving organelle fitness and cell function for life. Here, we provide an immunologist's perspective on how the heart solves this challenge, which is in part by incorporating macrophages as an integral component of the myocardium. Cardiac macrophages surround cardiomyocytes and capture dysfunctional mitochondria that these cells eject to the milieu, effectively establishing a client cell-support cell interaction. We refer to this heterologous partnership as heterophagy. Notably, this process shares analogies with other biological systems, is essential for proteostasis and metabolic fitness of cardiomyocytes, and unveils a remarkable degree of dependence of the healthy heart on immune cells for everyday function.

Cardiorespiratory Fitness and Cardiometabolic Risk Factors in Children and Adolescents From Southwest Colombia: Association Patterns Considering Adiposity.

BACKGROUND: Little is known about the cardiorespiratory fitness (CRF)-cardiometabolic risk relationship in Latin American pediatric populations across different age/sex groups, especially when considering the potential effects of adiposity on the association. We evaluated cross-sectional associations between VO2max and cardiometabolic risk variables (CMRV), and verified whether the associations were independent of adiposity markers in school-aged children and adolescents from Cali, Colombia. METHODS: The sample consisted of 1206 children aged 5-17 years. CMRV were fasting glucose, HDL and LDL cholesterol, triglycerides, systolic, and diastolic pressure. Logistic regressions were conducted for associations of age/sex-specific tertiles of VO2max with age/sex-specific highest tertiles of CMRV (except HDL-C, lowest tertile) and a CMR cluster (> 2 CMRV in extreme tertiles), adjusting for socioeconomic stratum, and adiposity markers (BMI, body fat percentage, and waist circumference). RESULTS: Overweight/obesity ranged from 15% to 18% with no difference by sex. In children aged 5-11 years, high VO2max (highest tertile vs. lowest) was inversely associated with the CMR cluster [Odds ratio (95% confidence interval): 0.18 (0.06-0.47), p < 0.05] independently of adjustment for any adiposity marker in boys but not in girls. In the age group of 12-17 years, there were initially significant VO2max- CMR cluster and VO2max- CMRV associations but attenuated by adiposity adjustment. In girls, high VO2max was inversely associated with high systolic blood pressure regardless of adjustment for adiposity markers. CONCLUSION: VO2max is inversely associated with cardiometabolic risk, but adiposity influences the association. The adiposity-independent association among younger boys requires further research. Interventions to tackle cardiometabolic risk in childhood may primarily focus on reducing excess adiposity, and secondarily on improvement of CRF.

Tuning the Electronic Response of Metallic Graphene by Potassium Doping.

Electron doping of graphene has been extensively studied on graphene-supported surfaces, where the metallicity is influenced by the substrate. Herewith we propose potassium adsorption on free-standing nanoporous graphene, thus eluding any effect due to the substrate. We monitor the electron migration in the π* downward-shifted conduction band. In this rigid band shift, we correlate the spectral density of the π* state in the upper Dirac cone with the associated plasmon, blue-shifted with increasing K dose, as deduced by electron energy loss spectroscopy. These results are confirmed by the Dirac plasmon activated by the C 1s emitted electrons, thanks to spatially resolved photoemission. This crosscheck constitutes a reference on the correlation between the electronic π* states in the conduction band and the Dirac plasmon evolution upon in situ electron doping of fully free-standing graphene.