Ying Guo

CD4(+) T cell responses are critical for the pathogenesis of Helicobacter pylori infection. The present study evaluated the role of the Th17 subset in H. pylori infection. H. pylori infection induced significant expression of IL-17 and IFN-gamma in mouse gastric tissue. IL-23 and IL-12 were increased in the gastric tissue and in H. pylori-stimulated macrophages. Cell responses were examined by intracellular staining for IFN-gamma, IL-4, and IL-17. Mice infected with H. pylori developed a mixed Th17/Th1 response; Th17 responses preceded Th1 responses. Treatment of mice with an anti-IL-17 Ab but not a control Ab significantly reduced the H. pylori burden and inflammation in the stomach. H. pylori colonization and gastric inflammation were also lower in IL-17(-/-) mice. Furthermore, administration of recombinant adenovirus encoding mouse IL-17 increased both H. pylori load and inflammation. Further analysis showed that the Th1 cell responses to H. pylori were downregulated when IL-17 is deficient. These results together suggest that H. pylori infection induces a mixed Th17/Th1 cell response and the Th17/IL-17 pathway modulates Th1 cell responses and contributes to pathology.

Monocyte-derived tumor-associated macrophages (Mo-TAMs) intensively infiltrate diffuse gliomas with remarkable heterogeneity. Using single-cell transcriptomics, we chart a spatially resolved transcriptional landscape of Mo-TAMs across 51 patients with isocitrate dehydrogenase (IDH)-wild-type glioblastomas or IDH-mutant gliomas. We characterize a Mo-TAM subset that is localized to the peri-necrotic niche and skewed by hypoxic niche cues to acquire a hypoxia response signature. Hypoxia-TAM destabilizes endothelial adherens junctions by activating adrenomedullin paracrine signaling, thereby stimulating a hyperpermeable neovasculature that hampers drug delivery in glioblastoma xenografts. Accordingly, genetic ablation or pharmacological blockade of adrenomedullin produced by Hypoxia-TAM restores vascular integrity, improves intratumoral concentration of the anti-tumor agent dabrafenib, and achieves combinatorial therapeutic benefits. Increased proportion of Hypoxia-TAM or adrenomedullin expression is predictive of tumor vessel hyperpermeability and a worse prognosis of glioblastoma. Our findings highlight Mo-TAM diversity and spatial niche-steered Mo-TAM reprogramming in diffuse gliomas and indicate potential therapeutics targeting Hypoxia-TAM to normalize tumor vasculature.

Helicobacter pylori infection is a risk factor for development of peptic ulcers, and psychological stress (PS) may have a role in the pathogenesis of this condition. However, no interaction between PS and H. pylori infection (HI) has been established in the development of peptic ulcer, because colonization by H. pylori is the first step in the infection of the gastric mucosa, we examined H. pylori colonization of the stomach in BALB/c mice after PS. The mice were subjected to PS in a communication box test, in which they observed other mice experiencing a physical stressor (electrical) before they were inoculated with H. pylori. We found that the H. pylori colonization in the stomach of psychologically stressed mice was significantly greater than in the control mice (P < 0.05), and histological examination showed that the gastric mucosal injury in the stressed mice was more extensive than in the control mice (P < 0.05). To explore the underlying mechanisms, we administered RU486 (a type II glucocorticoid (GC) receptor antagonist) to antagonize the effect of endogenous corticosterone: this treatment decreased colonization by H. pylori in the psychologically stressed mice. We conclude that HI of the stomach of BALB/c mice is enhanced by PS, and the effect may be mediated by GCs.