ABSTRACT
Oxygen is critical for all metazoan organisms on the earth and impacts various biological processes in physiological and pathological conditions. While oxygen-sensing systems inducing acute hypoxic responses, including the hypoxia-inducible factor pathway, have been identified, those operating in prolonged hypoxia remain to be elucidated. Here we show that pyridoxine 5'-phosphate oxidase (PNPO), which catalyses bioactivation of vitamin B6, serves as an oxygen sensor and regulates lysosomal activity in macrophages. Decreased PNPO activity under prolonged hypoxia reduced an active form of vitamin B6, pyridoxal 5'-phosphate (PLP), and inhibited lysosomal acidification, which in macrophages led to iron dysregulation, TET2 protein loss and delayed resolution of the inflammatory response. Among PLP-dependent metabolism, supersulfide synthesis was suppressed in prolonged hypoxia, resulting in the lysosomal inhibition and consequent proinflammatory phenotypes of macrophages. The PNPO-PLP axis creates a distinct layer of oxygen sensing that gradually shuts down PLP-dependent metabolism in response to prolonged oxygen deprivation.
Subject(s)
Lysosomes , Macrophages , Pyridoxal Phosphate , Lysosomes/metabolism , Macrophages/metabolism , Animals , Mice , Pyridoxal Phosphate/metabolism , Hypoxia/metabolism , Cell Hypoxia , Vitamin B 6/metabolism , Oxygen/metabolism , Inflammation/metabolismABSTRACT
BACKGROUND AND AIMS: Mosaic chromosomal alterations [mCAs] increase the risk for haematopoietic malignancies and may be risk factors for several other diseases. Inflammatory bowel diseases [IBDs], including Crohn's disease [CD] and ulcerative colitis [UC], are associated with mCAs, and patients may be at risk for haematopoietic malignancy development and/or modification of IBD phenotypes. In the present study, we screened patients with IBD for the presence of mCAs and explored the possible pathophysiological and genetic risk factors for mCAs. METHODS: We analysed mCAs in peripheral blood from 3339 patients with IBD and investigated the clinical and genetic risk factors for mCAs. RESULTS: CD and exposure to thiopurines before the age of 20 years were identified as novel independent risk factors for mCAs [odds ratio = 2.15 and 5.68, p = 1.17e-2 and 1.60e-3, respectively]. In contrast, there were no significant associations of disease duration, anti-tumour necrosis factor alpha antibodies, or other clinical factors with mCAs. Gene ontology enrichment analysis revealed that genes specifically located in the mCAs in patients with CD were significantly associated with factors related to mucosal immune responses. A genome-wide association study revealed that ERBIN, CD96, and AC068672.2 were significantly associated with mCAs in patients with CD [p = 1.56e-8, 1.65e-8, and 4.92e-8, respectively]. CONCLUSIONS: The difference in mCAs between patients with CD and UC supports the higher incidence of haematopoietic malignancies in CD. Caution should be exercised when using thiopurines in young patients with IBD, particularly CD, in light of possible chromosomal alterations.
Subject(s)
Colitis, Ulcerative , Crohn Disease , Hematologic Neoplasms , Inflammatory Bowel Diseases , Colitis, Ulcerative/complications , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/genetics , Crohn Disease/complications , Crohn Disease/drug therapy , Crohn Disease/genetics , Genome-Wide Association Study , Humans , Immunologic Factors , Inflammatory Bowel Diseases/complications , Risk FactorsABSTRACT
An 83-year-old man was detected to have solitary abdominal lymphadenopathy, and pathological findings revealed squamous cell carcinoma. Endoscopic examination revealed a depressive lesion in the middle thoracic esophagus. Endoscopic submucosal dissection was performed. Pathological findings revealed invasion to the lamina propria mucosae, negative vascular invasion, and surgical margins. At 8 months after metastatic lymphadenectomy, no recurrence was observed.