Abstract
Simple SummaryHypoxia-induced signalling represents an important contributor to inflammatory bowel disease (IBD) pathophysiology. However, available data solely focus on colonic inflammation while the primary disease location in Crohn’s disease patients is the terminal ileum. Therefore, we explored the effects of environmental hypoxia and immune cell-specific deletion of oxygen sensor prolyl hydroxylase (PHD) 1 in a Crohn’s like ileitis mouse model. Five-week-old TNF∆ARE/+ mice and wildtype (WT) littermates were housed in normoxia (21% O2) or hypoxia (8% O2) for 10 weeks. Although environmental hypoxia increased both systemic as ileal markers of hypoxia, the body weight evolution in both WT and TNF∆ARE/+ mice was not affected. Interestingly, hypoxia did increase circulatory monocytes, ileal mononuclear phagocytes and proinflammatory cytokine expression in WT mice. However, no histological or inflammatory gene expression differences in the ileum could be identified between TNF∆ARE/+ mice housed in hypoxia versus normoxia nor between TNF∆ARE/+ and WT mice with additional loss of immune cell-specific Phd1 expression. This is the first study showing that long-term environmental hypoxia or haematopoietic Phd1-deletion does not impact experimental ileitis. Therefore, it strongly questions whether targeting hypoxia-induced signalling via currently available PHD inhibitors would exert an immune suppressive effect in IBD patients with ileal inflammation.Environmental hypoxia and hypoxia-induced signalling in the gut influence inflammatory bowel disease pathogenesis, however data is limited to colitis. Hence, we investigated the effect of environmental hypoxia and immune cell-specific deletion of oxygen sensor prolyl hydroxylase (PHD) 1 in a Crohn’s like ileitis mouse model. Therefore, 5-week-old C57/BL6 TNF∆ARE/+ mice and wildtype (WT) littermates were housed in normoxia (21% O2) or hypoxia (8% O2) for 10 weeks. Systemic inflammation was assessed by haematology. Distal ileal hypoxia was evaluated by pimonidazole staining. The ileitis degree was scored on histology, characterized via qPCR and validated in haematopoietic Phd1-deficient TNF∆ARE/+ mice. Our results demonstrated that hypoxia did not impact body weight evolution in WT and TNF∆ARE/+ mice. Hypoxia increased red blood cell count, haemoglobin, haematocrit and increased pimonidazole intensity in the ileum. Interestingly, hypoxia evoked an increase in circulatory monocytes, ileal mononuclear phagocytes and proinflammatory cytokine expression in WT mice. Despite these alterations, no histological or ileal gene expression differences could be identified between TNF∆ARE/+ mice housed in hypoxia versus normoxia nor between haematopoietic Phd1-deficient TNF∆ARE/+ and their WT counterparts. Therefore, we demonstrated for the first time that long-term environmental hypoxia or haematopoietic Phd1-deletion does not impact experimental ileitis development.
Highlights
Inflammatory bowel diseases (IBD) are chronic, relapsing inflammatory disorders of the gastrointestinal tract, comprising Crohn’s disease (CD) and Ulcerative Colitis (UC) [1,2].The disease is characterized by a complex interplay of genetic, microbial and environmental factors that influence mucosal homeostasis and induce an inadequate immune response [2].Environmental hypoxia has been increasingly recognized as an important influence factor of IBD development
We aimed to evaluate the effect of environmental hypoxia and haematopoietic Phd1-deficiency during experimental Crohn’s like ileitis
No differences in spleen or liver weight could be identified at week 15 between TNF∆ARE/+ mice and WT littermates housed in hypoxia versus normoxia (Figure 1b,c)
Summary
Inflammatory bowel diseases (IBD) are chronic, relapsing inflammatory disorders of the gastrointestinal tract, comprising Crohn’s disease (CD) and Ulcerative Colitis (UC) [1,2].The disease is characterized by a complex interplay of genetic, microbial and environmental factors that influence mucosal homeostasis and induce an inadequate immune response [2].Environmental hypoxia has been increasingly recognized as an important influence factor of IBD development. Inflammatory bowel diseases (IBD) are chronic, relapsing inflammatory disorders of the gastrointestinal tract, comprising Crohn’s disease (CD) and Ulcerative Colitis (UC) [1,2]. The disease is characterized by a complex interplay of genetic, microbial and environmental factors that influence mucosal homeostasis and induce an inadequate immune response [2]. Environmental hypoxia has been increasingly recognized as an important influence factor of IBD development. 3 (NLRP3)/mammalian target of rapamycin (mTOR) binding [2]. Very interesting, these studies focused solely on colonic inflammation while in approximately two-thirds of CD cases, the primary location of inflammatory lesions is the small intestine, the terminal ileum [4]. The impact of environmental hypoxia on chronic ileitis onset and course remains elusive
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