How commensal microbiota contributes to immune cell homeostasis at barrier surfaces is poorly understood. Lamina propria (LP) T helper 17 (Th17) cells participate in mucosal protection and are ...induced by commensal segmented filamentous bacteria (SFB). Here we show that MHCII-dependent antigen presentation of SFB antigens by intestinal dendritic cells (DCs) is crucial for Th17 cell induction. Expression of MHCII on CD11c+ cells was necessary and sufficient for SFB-induced Th17 cell differentiation. Most SFB-induced Th17 cells recognized SFB in an MHCII-dependent manner. SFB primed and induced Th17 cells locally in the LP and Th17 cell induction occurred normally in mice lacking secondary lymphoid organs. The importance of other innate cells was unveiled by the finding that MHCII deficiency in group 3 innate lymphoid cells (ILCs) resulted in an increase in SFB-independent Th17 cell differentiation. Our results outline the complex role of DCs and ILCs in the regulation of intestinal Th17 cell homeostasis.
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•Presentation of SFB antigens by iDC is required for Th17 cell induction by SFB•SFB-induced Th17 cells recognize SFB antigens•SFB prime CD4 T cells and induce Th17 cell differentiation in the gut mucosa•Loss of MHCII on RORγt ILC leads to Th17 cell differentiation in the absence of SFB
Circulating levels of undercarboxylated and bioactive osteocalcin double during aerobic exercise at the time levels of insulin decrease. In contrast, circulating levels of osteocalcin plummet early ...during adulthood in mice, monkeys, and humans of both genders. Exploring these observations revealed that osteocalcin signaling in myofibers is necessary for adaptation to exercise by favoring uptake and catabolism of glucose and fatty acids, the main nutrients of myofibers. Osteocalcin signaling in myofibers also accounts for most of the exercise-induced release of interleukin-6, a myokine that promotes adaptation to exercise in part by driving the generation of bioactive osteocalcin. We further show that exogenous osteocalcin is sufficient to enhance the exercise capacity of young mice and to restore to 15-month-old mice the exercise capacity of 3-month-old mice. This study uncovers a bone-to-muscle feedforward endocrine axis that favors adaptation to exercise and can reverse the age-induced decline in exercise capacity.
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•Bone via the hormone osteocalcin improves muscle function during exercise•Circulating osteocalcin levels decrease in aging mice, monkeys, and humans•Osteocalcin promotes muscle uptake and utilization of glucose and fatty acids•Osteocalcin promotes muscle IL-6 secretion during exercise
Mera et al. show that the bone-derived hormone osteocalcin is necessary for optimum exercise capacity and that this hormone decreases with aging in mice, monkeys, and humans of both genders. Osteocalcin promotes muscle uptake and utilization of glucose and lipids during exercise and greatly improves the exercise capacity of old mice.
Remodeling of the microenvironment by tumor cells can activate pathways that favor cancer growth. Molecular delineation and targeting of such malignant-cell nonautonomous pathways may help overcome ...resistance to targeted therapies. Herein we leverage genetic mouse models, patient-derived xenografts, and patient samples to show that acute myeloid leukemia (AML) exploits peripheral serotonin signaling to remodel the endosteal niche to its advantage. AML progression requires the presence of serotonin receptor 1B (HTR1B) in osteoblasts and is driven by AML-secreted kynurenine, which acts as an oncometabolite and HTR1B ligand. AML cells utilize kynurenine to induce a proinflammatory state in osteoblasts that, through the acute-phase protein serum amyloid A (SAA), acts in a positive feedback loop on leukemia cells by increasing expression of IDO1-the rate-limiting enzyme for kynurenine synthesis-thereby enabling AML progression. This leukemia-osteoblast cross-talk, conferred by the kynurenine-HTR1B-SAA-IDO1 axis, could be exploited as a niche-focused therapeutic approach against AML, opening new avenues for cancer treatment.
AML remains recalcitrant to treatments due to the emergence of resistant clones. We show a leukemia-cell nonautonomous progression mechanism that involves activation of a kynurenine-HTR1B-SAA-IDO1 axis between AML cells and osteoblasts. Targeting the niche by interrupting this axis can be pharmacologically harnessed to hamper AML progression and overcome therapy resistance. This article is highlighted in the In This Issue feature, p. 873.
The bone marrow niche is thought to act as a permissive microenvironment required for emergence or progression of hematologic cancers. We hypothesized that osteoblasts, components of the niche ...involved in hematopoietic stem cell (HSC) function, influence the fate of leukemic blasts. We show that osteoblast numbers decrease by 55% in myelodysplasia and acute myeloid leukemia patients. Further, genetic depletion of osteoblasts in mouse models of acute leukemia increased circulating blasts and tumor engraftment in the marrow and spleen leading to higher tumor burden and shorter survival. Myelopoiesis increased and was coupled with a reduction in B lymphopoiesis and compromised erythropoiesis, suggesting that hematopoietic lineage/progression was altered. Treatment of mice with acute myeloid or lymphoblastic leukemia with a pharmacologic inhibitor of the synthesis of duodenal serotonin, a hormone suppressing osteoblast numbers, inhibited loss of osteoblasts. Maintenance of the osteoblast pool restored normal marrow function, reduced tumor burden, and prolonged survival. Leukemia prevention was attributable to maintenance of osteoblast numbers because inhibition of serotonin receptors alone in leukemic blasts did not affect leukemia progression. These results suggest that osteoblasts play a fundamental role in propagating leukemia in the marrow and may be a therapeutic target to induce hostility of the niche to leukemia blasts.
•Acute myeloid leukemia decreases osteoblast numbers in humans and mice.•Reinstatement of osteoblast number and function in leukemic mice by a pharmacologic approach reduces tumor burden in all sites and prolongs survival.
Segmented filamentous bacteria (SFB) are Gram-positive, anaerobic, spore-forming commensals that reside in the gut of many animal species. Described more than forty years ago, SFB have recently ...gained interest due to their unique ability to modulate the host immune system through induction of IgA and Th17 cells. Here, we describe a collection of methods to detect and quantify SFB and SFB adhesion in intestinal mucosa, as well as SFB-specific CD4 T cells in the lamina propria. In addition, we describe methods for purification of SFB from fecal material of SFB-monoassociated gnotobiotic mice. Using these methods we examine the kinetics of SFB colonization and Th17 cell induction. We also show that SFB colonize unevenly the intestinal mucosa and that SFB adherence occurs predominantly in the terminal ileum and correlates with an increased proportion of SFB-specific Th17 cells.
•SFB colonization and Th17 cell induction follow defined kinetics.•SFB are distributed unevenly along the length of the small intestine.•SFB-specific Th17 cells are enriched in the terminal ileum.•Th17 cell induction in the small intestine correlates with SFB adherence.
Hematopoietic stem cells (HSCs) reside and are maintained in specialized microenvironments within the bone marrow known as niches, which are comprised of various cell types. Among them, leptin ...receptor (LepR)-expressing CXC chemokine ligand 12 (CXCL12)-abundant reticular (CAR) cells are known to create a niche for HSCs and at the same time to give rise to osteoblasts. These two functions of CAR/LepR
cells appear to be tightly but inversely regulated to ensure adequate physical space for HSCs. However, how osteogenesis is prevented in CAR cells to maintain spaces available for HSCs and hematopoiesis remains unclear. In this issue of
, Seike and colleagues (pp. 359-372) report that the transcription factor early B-cell factor (
) is preferentially expressed by CAR/LepR
cells and inhibits CAR cell differentiation into osteoblasts while at the same time maintaining self-renewal of CAR/LepR
cells. Using conditional knockout and retroviral systems, the investigators show that loss of
in CAR cells impairs HSC numbers and leads to osteosclerosis. This study provides novel insights into transcriptional requirements for CAR cell bone formation by identifying Ebf3 as a niche factor secreted from CAR/Lepr
cells that regulates the interplay between osteogenesis and hematopoiesis.
Hematopoietic stem cells (HSCs) interact dynamically with an intricate network of cells in the bone marrow (BM) microenvironment or niche. These interactions provide instructive cues that influence ...the production and lineage determination of different types of blood cells and maintenance of HSC quiescence. They also contribute to hematopoietic deregulation and hematological myeloid malignancies. Alterations in the BM niche are commonly observed in myeloid malignancies and contribute to the aberrant function of myelodysplastic and leukemia-initiating stem cells. In this work, we review how different components of the BM niche affect normal hematopoiesis, the molecular signals that govern this interaction, and how genetic changes in stromal cells or alterations in remodeled malignant BM niches contribute to myeloid malignancies. Understanding the intricacies between normal and malignant niches and their modulation may provide insights into developing novel therapeutics for blood disorders.
Innate immunity to Candida albicans depends upon the recognition of molecular patterns on the fungal cell wall. However, the masking of major components such as β-glucan seems to be a mechanism that ...fungi have evolved to avoid immune cell recognition through the dectin-1 receptor. Although the role of C. albicans mitogen-activated protein kinase (MAPK) pathways as virulence determinants has been established previously with animal models, the mechanism involved in this behavior is largely unknown. In this study we demonstrate that a disruption of the C. albicans extracellular signal-regulated kinase (ERK)-like 1 (CEK1)-mediated MAPK pathway causes enhanced cell wall β-glucan exposure, triggering immune responses more efficiently than the wild type, as measured by dectin-1-mediated specific binding and human dendritic cell (hDC)- and macrophage-mediated phagocytosis, killing, and activation of intracellular signaling pathways. At the molecular level, the disruption of CEK1 resulted in altered spleen tyrosine kinase (Syk), Raf-1, and ERK1/2 activations together with IκB degradation on hDCs and increased dectin-1-dependent activator protein 1 (AP-1) activation on transfected cells. In addition, concurring with these altered pathways, we detected increased reactive oxygen species production and cytokine secretion. In conclusion, the CEK1-mediated MAPK pathway is involved in β-glucan exposure in a fungal pathogen, hence influencing dectin-1-dependent immune cell recognition, thus establishing this fungal intracellular signaling route as a promising novel therapeutic target.
Patients with myelodysplasia or acute myeloid leukemia (AML) show decreased osteoblast numbers, and this is reproduced in mouse models of acute leukemia. Manipulating the osteoblast pool directly ...affects leukemia progression: osteoblast ablation increases leukemia burden, while maintenance of osteoblast numbers decreases it and prolongs survival. Here we show that the protective effect of osteoblasts against leukemia does not rely on a certain threshold of osteoblast numbers but rather requires a specific signaling pathway. Treatment of leukemic mice with parathyroid hormone, which increases osteoblast numbers, had no effect in leukemia progression. In contrast, maintaining the osteoblast pool in leukemic mice by decreasing the synthesis of gut-derived serotonin, reduced AML burden and prolonged survival. Using the human-AML MLL-AF9 model, we examined whether deletion of one of the main serotonin receptors expressed in osteoblasts affects leukemia progression. Global deletion of Htr1b in mice prevented leukemia. While removal of Htr1b in LepR+ positive mesenchymal stem cells had no effect in leukemia progression, its deletion in Col1a1-expressing osteoblast precursors significantly prevented lethality in the mutant mice. In order to dissect the crosstalk between leukemia-cells and osteoblasts, we co-cultured primary-human osteoblasts and AML cells. RNAseq analysis identified a signature of chemoattractants and pro-inflammatory cytokines secreted by osteoblasts upon exposure to AML cells, suggesting that the protective mechanism exerted by osteoblasts activates the anti-tumor immune response against leukemia. In summary, our data suggest that AML cells activate serotonin signaling in osteoblasts to promote their engraftment and expansion. Targeting this pathway may render the niche hostile to leukemia by enhancing the anti-tumor immune response elicited by osteoblasts.
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