Summary Trained innate immunity, induced via modulation of mature myeloid cells or their bone marrow progenitors, mediates sustained increased responsiveness to secondary challenges. Here, we investigated whether anti-tumor immunity can be enhanced through induction of trained immunity. Pre-treatment of mice with β-glucan, a fungal-derived prototypical agonist of trained immunity, resulted in diminished tumor growth. The anti-tumor effect of β-glucan-induced trained immunity was associated with transcriptomic and epigenetic rewiring of granulopoiesis and neutrophil reprogramming toward an anti-tumor phenotype; this process required type I interferon signaling irrespective of adaptive immunity in the host. Adoptive transfer of neutrophils from β-glucan-trained mice to naive recipients suppressed tumor growth in the latter in a ROS-dependent manner. Moreover, the anti-tumor effect of β-glucan-induced trained granulopoiesis was transmissible by bone marrow transplantation to recipient naive mice. Our findings identify a novel and therapeutically relevant anti-tumor facet of trained immunity involving appropriate rewiring of granulopoiesis.

Oxidatively modified low-density lipoprotein (oxLDL) plays a key role in the initiation of atherosclerosis by increasing monocyte adhesion. The mechanism that is responsible for the oxLDL-induced atherogenic monocyte recruitment in vivo, however, still remains unknown. Oxidation of LDL generates lysophosphatidylcholine, which is the main substrate for the lysophosphatidic acid (LPA) generating enzyme autotaxin. We show that oxLDL requires endothelial LPA receptors and autotaxin to elicit CXCL1-dependent arterial monocyte adhesion. Unsaturated LPA releases endothelial CXCL1, which is subsequently immobilized on the cell surface and mediates LPA-induced monocyte adhesion. Local and systemic application of LPA accelerates the progression of atherosclerosis in mice. Blocking the LPA receptors LPA(1) and LPA(3) reduced hyperlipidemia-induced arterial leukocyte arrest and atherosclerosis in the presence of functional CXCL1. Thus, atherogenic monocyte recruitment mediated by hyperlipidemia and modified LDL crucially depends on LPA, which triggers endothelial deposition of CXCL1, revealing LPA signaling as a target for cardiovascular disease treatments.

es. We show that Del-1, via its interaction with the αvβ3 integrin, promotes several critical functions in the niche, including HSC retention, hematopoietic progenitor cell cycle progression, and myeloid lineage commitment of HSCs. Del-1 thereby regulates myelopoiesis under steady-state conditions and in G-CSF-or inflammation-induced stress myelopoiesis, as well as myelopoiesis reconstitution under regenerative/transplantation conditions. Del-1 is hence a niche component that serves a juxtacrine homeostatic adaptation of the hematopoietic system in inflammation-related and regeneration myelopoiesis. ResultsDel-1 expression in the BM. First, we sought to investigate whether Del-1 is present in the BM. We initially studied the expression of the Del-1-encoding gene Edil3 in the BM niche and hematopoietic cell populations. We found that Edil3 mRNA expression was significantly higher in the endosteal region as compared with the central BM (cBM) ( Figure 1A), suggesting that Del-1 is enriched at the endosteal area of the BM. Analysis of sorted cells from CXCL12-GFP mice (33, 34) demonstrated that Edil3 was highly expressed integrin receptors (29-31). It consists of three N-terminal EGF-like repeats and two C-terminal discoidin I-like domains, and hence also is designated EGF-like repeats and discoidin-I-like domains-3 (EDIL3) (32). We have previously identified Del-1 as an endogenous modulator of leukocyte adhesion through interaction with integrin αLβ2 (LFA-1; CD11a/CD18) (29, 31). Moreover, Del-1 interacts with β3 integrin (CD61) via an Arg-Gly-Asp (RGD) motif on the second EGF-like repeat (30).In the present work, we observed that Del-1 is expressed by several major cellular components of the HSC niche, though not by hematopoietic progenitors. In particular, Del-1 is expressed by those niche cells that have a major role in the maintenance of HSCs, i.e., arteriolar endothelial cells and perivascular CAR cells (3,6,7,9,15). In addition, Del-1 is expressed by cells of the osteoblastic lineage that crucially mediate the engraftment of HSCs in the post-transplantation niche (3,17,18). This spatial distribution of Del-1 raised the possibility that it might be involved in the regulation of hematopoiesis. We addressed this hypothesis using in vivo models of steady-state, regenerative, and stress hematopoiesis and in vitro mechanistic approach-

ObjectiveThe rs641738C>T variant located near the membrane-bound O-acyltransferase domain containing 7 (MBOAT7) locus is associated with fibrosis in liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease, hepatitis B and C. We aim to understand the mechanism by which the rs641738C>T variant contributes to pathogenesis of NAFLD.DesignMice with hepatocyte-specific deletion of MBOAT7 (Mboat7Δhep) were generated and livers were characterised by histology, flow cytometry, qPCR, RNA sequencing and lipidomics. We analysed the association of rs641738C>T genotype with liver inflammation and fibrosis in 846 NAFLD patients and obtained genotype-specific liver lipidomes from 280 human biopsies.ResultsAllelic imbalance analysis of heterozygous human liver samples pointed to lower expression of the MBOAT7 transcript on the rs641738C>T haplotype. Mboat7Δhep mice showed spontaneous steatosis characterised by increased hepatic cholesterol ester content after 10 weeks. After 6 weeks on a high fat, methionine-low, choline-deficient diet, mice developed increased hepatic fibrosis as measured by picrosirius staining (p<0.05), hydroxyproline content (p<0.05) and transcriptomics, while the inflammatory cell populations and inflammatory mediators were minimally affected. In a human biopsied NAFLD cohort, MBOAT7 rs641738C>T was associated with fibrosis (p=0.004) independent of the presence of histological inflammation. Liver lipidomes of Mboat7Δhep mice and human rs641738TT carriers with fibrosis showed increased total lysophosphatidylinositol levels. The altered lysophosphatidylinositol and phosphatidylinositol subspecies in MBOAT7Δhep livers and human rs641738TT carriers were similar.ConclusionMboat7 deficiency in mice and human points to an inflammation-independent pathway of liver fibrosis that may be mediated by lipid signalling and a potentially targetable treatment option in NAFLD.

Chemokines mediate monocyte adhesion to dysfunctional endothelial cells (ECs) and promote arterial inflammation during atherosclerosis. Hypoxia-inducible factor (HIF)-1α is expressed in various cell types of atherosclerotic lesions and is associated with lesional inflammation. However, the impact of endothelial HIF-1α in atherosclerosis is unclear. HIF-1α was detectable in the nucleus of ECs covering murine and human atherosclerotic lesions. To study the role of endothelial HIF-1α in atherosclerosis, deletion of the Hif1 a gene was induced in ECs from apolipoprotein E knockout mice (EC- Hif1a −/− ) by Tamoxifen injection. The formation of atherosclerotic lesions, the lesional macrophage accumulation, and the expression of CXCL1 in ECs were reduced after partial carotid ligation in EC- Hif1a −/− compared with control mice. Moreover, the lesion area and the lesional macrophage accumulation were decreased in the aortas of EC- Hif1a −/− mice compared with control mice during diet-induced atherosclerosis. In vitro, mildly oxidized low-density lipoprotein or lysophosphatidic acid 20:4 increased endothelial CXCL1 expression and monocyte adhesion by inducing HIF-1α expression. Moreover, endothelial Hif1a deficiency resulted in downregulation of miR-19a in atherosclerotic arteries determined by microRNA profiling. In vitro, HIF-1α–induced miR-19a expression mediated the upregulation of CXCL1 in mildly oxidized low-density lipoprotein–stimulated ECs. These results indicate that hyperlipidemia upregulates HIF-1α expression in ECs by mildly oxidized low-density lipoprotein–derived unsaturated lysophosphatidic acid. Endothelial HIF-1α promoted atherosclerosis by triggering miR-19a–mediated CXCL1 expression and monocyte adhesion, indicating that inhibition of the endothelial HIF-1α/miR-19a pathway may be a therapeutic option against atherosclerosis.