RESUMO
Epithelial cells secrete chloride to regulate water release at mucosal barriers, supporting both homeostatic hydration and the "weep" response that is critical for type 2 immune defense against parasitic worms (helminths). Epithelial tuft cells in the small intestine sense helminths and release cytokines and lipids to activate type 2 immune cells, but whether they regulate epithelial secretion is unknown. Here, we found that tuft cell activation rapidly induced epithelial chloride secretion in the small intestine. This response required tuft cell sensory functions and tuft cell-derived acetylcholine (ACh), which acted directly on neighboring epithelial cells to stimulate chloride secretion, independent of neurons. Maximal tuft cell-induced chloride secretion coincided with immune restriction of helminths, and clearance was delayed in mice lacking tuft cell-derived ACh, despite normal type 2 inflammation. Thus, we have uncovered an epithelium-intrinsic response unit that uses ACh to couple tuft cell sensing to the secretory defenses of neighboring epithelial cells.
Assuntos
Acetilcolina , Cloretos , Células Epiteliais , Mucosa Intestinal , Animais , Acetilcolina/metabolismo , Camundongos , Cloretos/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/parasitologia , Células Epiteliais/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/parasitologia , Intestino Delgado/imunologia , Intestino Delgado/parasitologia , Intestino Delgado/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células em TufoRESUMO
Oxidative stress is a defining feature of most cancers, including those that stem from carcinogenic infections. Reactive oxygen species can drive tumor formation, yet the molecular oxidation events that contribute to tumorigenesis are largely unknown. Here we show that inactivation of a single, redox-sensitive cysteine in the host protease legumain, which is oxidized during infection with the gastric cancer-causing bacterium Helicobacter pylori, accelerates tumor growth. By using chemical proteomics to map cysteine reactivity in human gastric cells, we determined that H. pylori infection induces oxidation of legumain at Cys219. Legumain oxidation dysregulates intracellular legumain processing and decreases the activity of the enzyme in H. pylori-infected cells. We further show that the site-specific loss of Cys219 reactivity increases tumor growth and mortality in a xenograft model. Our findings establish a link between an infection-induced oxidation site and tumorigenesis while underscoring the importance of cysteine reactivity in tumor growth.
Assuntos
Cisteína Endopeptidases , Infecções por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Transformação Celular Neoplásica/metabolismo , Cisteína/metabolismo , Cisteína Endopeptidases/metabolismo , Humanos , Oxirredução , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologiaRESUMO
Tuft cells are specialized taste-chemosensory cells that detect the presence of intestinal parasites and orchestrate type 2 immunity. In this issue of Immunity, McGinty et al. discover that parasitic worms, but not commensal protists, stimulate tuft cells to release cysteinyl leukotrienes to amplify anti-helminth immunity in the small intestine.
Assuntos
Helmintos , Mebendazol , Animais , Mucosa Intestinal , Intestino Delgado , LeucotrienosRESUMO
Lifelong infection of the gastric mucosa by Helicobacter pylori can lead to peptic ulcers and gastric cancer. However, how the bacteria maintain chronic colonization in the face of constant mucus and epithelial cell turnover in the stomach is unclear. Here, we present a new model of how H. pylori establish and persist in stomach, which involves the colonization of a specialized microenvironment, or microniche, deep in the gastric glands. Using quantitative three-dimensional (3D) confocal microscopy and passive CLARITY technique (PACT), which renders tissues optically transparent, we analyzed intact stomachs from mice infected with a mixture of isogenic, fluorescent H. pylori strains with unprecedented spatial resolution. We discovered that a small number of bacterial founders initially establish colonies deep in the gastric glands and then expand to colonize adjacent glands, forming clonal population islands that persist over time. Gland-associated populations do not intermix with free-swimming bacteria in the surface mucus, and they compete for space and prevent newcomers from establishing in the stomach. Furthermore, bacterial mutants deficient in gland colonization are outcompeted by wild-type (WT) bacteria. Finally, we found that host factors such as the age at infection and T-cell responses control bacterial density within the glands. Collectively, our results demonstrate that microniches in the gastric glands house a persistent H. pylori reservoir, which we propose replenishes the more transient bacterial populations in the superficial mucosa.
Assuntos
Mucosa Gástrica/microbiologia , Helicobacter pylori/crescimento & desenvolvimento , Microscopia Confocal/métodos , Animais , Antibacterianos/farmacologia , Linhagem Celular Tumoral , Contagem de Colônia Microbiana , Feminino , Mucosa Gástrica/efeitos dos fármacos , Infecções por Helicobacter/microbiologia , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/genética , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação/genética , Especificidade da Espécie , Linfócitos T/efeitos dos fármacosRESUMO
Palliative care patients experience a variety of needs and perceive their quality of life as being only fair. This study adopted a single-group repeated-measure design to investigate the effect of horticultural therapy on the quality of life of palliative care patients using the Quality of Life Concern in End of Life Questionnaire. Significant differences in the domains of "existential distress" and "health care concern" were observed immediately postintervention and at 4 weeks postintervention, respectively. No other significant differences were seen in the other domains or in the total mean score of the outcome measure.