Plasmacytoid Dendritic Cell-Derived Type I Interferon Is Involved in Helicobacter pylori Infection-Induced Differentiation of Schlafen 4-Expressing Myeloid-Derived Suppressor Cells.

During chronic infection with Helicobacter pylori, Schlafen 4-expressing myeloid-derived suppressor cells (SLFN4+ MDSCs) create a microenvironment favoring intestinal metaplasia and neoplastic transformation. SLFN4 can be induced by alpha interferon (IFN-α), which is mainly secreted from plasmacytoid dendritic cells (pDCs). This study tested the hypothesis that Helicobacter pylori infection promotes SLFN4+ MDSC differentiation by inducing pDCs to secrete IFN-α. C57BL/6 mice were gavaged with H. pylori, and infection lasted 2, 4, or 6 months. Mouse pDCs were isolated from bone marrow of wild-type C57BL/6J mice. The results showed that H. pylori infection increased the number of SLFN4+ MDSCs by inducing IFN-α expression in mice. Further mechanistic experiments unraveled that IFN-α induced SLFN4 transcription by binding to the Slfn4 promoter. Furthermore, H. pylori infection stimulated pDCs to secrete IFN-α by activating the TLR9-MyD88-IRF7 pathway. Collectively, Helicobacter pylori infection promotes SLFN4+ MDSC differentiation by inducing secretion of IFN-α from pDCs.

Slfn4 deficiency improves MAPK-mediated inflammation, oxidative stress, apoptosis and abates atherosclerosis progression in apolipoprotein E-deficient mice.

BACKGROUND AND AIMS: Atherosclerosis, a progressive inflammatory disease characterized by elevated inflammation and lipid accumulation in the aortic endothelium, arises in part from the infiltration of inflammatory cells into the vascular wall. However, it is not fully defined how inflammatory cells, especially macrophages, affect the pathogenesis of atherosclerosis. Schlafen4 (Slfn4) mRNA is remarkably upregulated upon ox-LDL stimulation in macrophages. Nonetheless, the role of Slfn4 in foam cell formation remains unclear. METHODS: To determine whether and how Slfn4 regulates lesion macrophage function during atherosclerosis，we engineered ApoE-/-Slfn4-/- double-deficient mice on an ApoE-/- background and evaluated the deficiency of Slfn4 expression in atherosclerotic lesion formation in vivo. RESULTS: Our results demonstrate that total absence of SLFN4 and the bone marrow-restricted deletion of Slfn4 in ApoE-/- mice remarkably diminish inflammatory cell numbers within arterial plaques as well as limit development of atherosclerosis in moderate hypercholesterolemia condition. This is linked to a marked reduction in the expression of proinflammatory cytokines, the generation of the reactive oxygen species (ROS) and the apoptosis of cells. Furthermore, the activation of MAPKs and apoptosis signaling pathways is compromised in the absence of Slfn4. CONCLUSIONS: These findings demonstrate a novel role of Slfn4 in modulating vascular inflammation and atherosclerosis, highlighting a new target for the related diseases.

Hedgehog Signaling Links Chronic Inflammation to Gastric Cancer Precursor Lesions.

Since its initial discovery in Drosophila, Hedgehog (HH) signaling has long been associated with foregut development. The mammalian genome expresses 3 HH ligands, with sonic hedgehog (SHH) levels highest in the mucosa of the embryonic foregut. More recently, interest in the pathway has shifted to improving our understanding of its role in gastrointestinal cancers. The use of reporter mice proved instrumental in our ability to probe the expression pattern of SHH ligand and the cell types responding to canonical HH signaling during homeostasis, inflammation, and neoplastic transformation. SHH is highly expressed in parietal cells and is required for these cells to produce gastric acid. Furthermore, myofibroblasts are the predominant cell type responding to HH ligand in the uninfected stomach. Chronic infection caused by Helicobacter pylori and associated inflammation induces parietal cell atrophy and the expansion of metaplastic cell types, a precursor to gastric cancer in human subjects. During Helicobacter infection in mice, canonical HH signaling is required for inflammatory cells to be recruited from the bone marrow to the stomach and for metaplastic development. Specifically, polarization of the invading myeloid cells to myeloid-derived suppressor cells requires the HH-regulated transcription factor GLI1, thereby creating a microenvironment favoring wound healing and neoplastic transformation. In mice, GLI1 mediates the phenotypic shift to gastric myeloid-derived suppressor cells by directly inducing Schlafen 4 (slfn4). However, the human homologs of SLFN4, designated SLFN5 and SLFN12L, also correlate with intestinal metaplasia and could be used as biomarkers to predict the subset of individuals who might progress to gastric cancer and benefit from treatment with HH antagonists.