ON THE COVER
Hulsmans et al. report that cardiac macrophages expand in left ventricular diastolic dysfunction, a hallmark of heart failure with preserved ejection fraction (HFpEF) and cardiac aging. In HFpEF, macrophages shift toward a profibrotic subset that promotes ventricular stiffness. Th e cover illustrates Mac3+ macrophages in the left ventricle of a mouse with hypertension-induced diastolic dysfunction. The image was provided by the authors and modified by the JEM editorial office. See page 423.
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Cardiac-resident macrophages are a diverse population of cells that have a critical role in the pathogenesis of heart failure. A new understanding of communication between macrophages and cardiac fibroblasts could lead to novel therapeutic strategies for heart failure with preserved ejection function.
Bile acids were recently shown to regulate glucose homeostasis through diverse mechanisms involving the host and its microbiome. Herein, Shapiro et al. discuss the impact of bile acids on normal and impaired glycemic responses, including potential therapeutic implications in treating hyperglycemia and diabetes.
The brain is our computing machine that integrates stimuli from the environment and orchestrates responses to these stimuli. Here, Jonathan Kipnis proposes that the defining role of the immune system is to sense microorganisms and to inform the brain about them.
Brief Definitive Report
Clarke et al. demonstrate that the innate-like B1 B cell subset has a distinct metabolic phenotype, characterized by high levels of glycolysis, pentose phosphate pathway, and TCA cycle activity, and depends on autophagy for metabolic homeostasis and self-renewal.
Factors that control skin inflammation are still being defined. Herro et al. demonstrate that the tumor necrosis factor superfamily protein LIGHT acts on keratinocytes via its receptor HVEM to promote characteristic features of atopic dermatitis, including epidermal hyperplasia and production of periostin.
Hulsmans et al. show that cardiac macrophages expand in left ventricular diastolic dysfunction, a hallmark of heart failure with preserved ejection fraction (HFpEF) and cardiac aging. In HFpEF, macrophages shift toward a profibrotic subset that promotes ventricular stiffness.
Bujko et al. describe four distinct subsets of macrophages in human small intestine that are completely replaced in transplanted duodenum. These subsets show graduated changes in their phenotypes, function, and transcriptome profiles, suggesting that they represent stages of monocyte-derived macrophage maturation in tissue.
There are very few human MAIT cells in cord blood. Ben Youssef et al. show that they slowly expand during childhood and point to a critical role of the TCRαβ repertoire in determining their unique ability to recognize MR1-restricted microbial antigens.
Capucha et al. demonstrate that mucosal Langerhans cell (LC) differentiation from pre–dendritic cells and monocytes involves consecutive BMP7 and TGF-β1 signaling in separate anatomical locations. Moreover, mucosal microbiota regulates the development of LCs that in turn shape microbial and immunological homeostasis.
Development of intestinal M cells and follicle-associated epithelium is regulated by TRAF6-mediated NF-κB signaling
TRAF6 is essential for RANK-mediated NF-κB activation and is involved in the development of several types of cells. Kanaya et al. demonstrate that RANK–TRAF6-mediated NF-κB is essential for the development of M cells and FAE.
The role of γδ T cells in spinal cord injury remains unknown. Sun et al. report that Vγ4 γδ T cells produce IFN-γ, promote inflammatory cytokine production of macrophages, and are detrimental for functional recovery after SCI.
Plasmacytoid dendritic cells protect from viral bronchiolitis and asthma through semaphorin 4a–mediated T reg expansion
Lynch et al. provide evidence of a causal relationship between RSV-bronchiolitis and asthma development and highlight a common but age-related Sema4a-mediated pathway by which pDCs and microbial colonization induce T reg cell expansion to confer protection against severe bronchiolitis and asthma.
Xiao et al. demonstrate that formation of super-enhancers at Il9 locus is critical for robust IL-9 expression and Th9 cell induction, and assembly of Il9 super-enhancers is driven by OX40-mediated chromatin acetylation.
Continuous activity of Foxo1 is required to prevent anergy and maintain the memory state of CD8+ T cells
Delpoux et al. show, in a model of latent infection, how FOXO1 is required to prevent apoptosis, the acquisition of an anergy phenotype, and to be constantly expressed for maintaining the differentiation state of CD8+ T cells.
Tenno et al. show that an evolutionarily conserved alternative splicing event in the Cbfb gene generates Cbfβ2, which forms a functionally distinct transcription factor complex underlying the differentiation of extrathymic T cell progenitors, including induction of the principal thymus-homing receptor, Ccr9.
Seki et al. show that ablation of endothelial VEGFR1 induces adipose tissues browning in healthy and obese mice, which has profound effects on improving global metabolic dysfunctions. These discoveries establish an important role for the adipose vasculature in controlling the metabolic functions of adipocytes and provide new therapeutic options for treatment of obesity and diabetes.
Obesity alters the long-term fitness of the hematopoietic stem cell compartment through modulation of Gfi1 expression
Lee et al. show that established obesity alters the composition and long-term fitness of the hematopoietic stem cell (HSC) compartment, in part through a Gfi1-dependent HSC regulatory program that is activated by the chronic oxidative stress associated with this condition.
Maturation of hematopoietic stem cells from prehematopoietic stem cells is accompanied by up-regulation of PD-L1
Tober et al. show that hematopoietic stem cells (HSCs) that mature from pre-HSCs in vivo in the fetal liver, versus ex vivo, are not molecularly equivalent. Although both express cell surface programmed death ligand 1 (PD-L1), it is not required for the engraftment of fetal HSCs into adult recipients.
Iron modulation of erythropoiesis is associated with Scribble-mediated control of the erythropoietin receptor
Iron deficiency causes resistance in erythroid progenitors against proliferative but not survival signals of erythropoietin. Khalil et al. link this response to the down-regulation of Scribble, an orchestrator of receptor trafficking and signaling. With iron deprivation, transferrin receptor 2 drives Scribble degradation, reconfiguring erythropoietin receptor function.
Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia
Tissino et al. demonstrate that in chronic lymphocytic leukemia, the VLA-4 (CD49d/CD29) integrin remains activable by B cell receptor stimulation also upon in vitro and in vivo ibrutinib exposure. Clinically, ibrutinib-treated CD49d-positive CLL patients experience reduced recirculation lymphocytosis and nodal response and inferior outcomes.
Jiao et al. show that the key player of antiviral immunity IRF3 binds to and promotes the transactivation of the YAP–TEAD4 complex to coregulate transcription of Hippo pathway target genes and that therapeutic targeting of IRF3 suppresses YAP-driven gastric cancer.