Pathomechanismus des Morbus Crohn mit NOD-2 (CARD 15) Mutation: defiziente mukosale Defensinexpression bei intakter Zytokinexpression

Wehkamp, Jan; Harder, J; Weichenthal, Michael; Herrlinger, K; Schmidt, Maxine; Schlee, Miriam; Nuding, Sebastian; Schwab, M.; Schäffeler, Elke; Stallmach, Andreas; Fellermann, Klaus; Jm, Schröder; Ef, Stange

doi:10.1055/s-0035-1555178

Cited by 4 publications

(4 citation statements)

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“…HD5 is the primary antimicrobial peptide released into the human intestinal lumen, which plays a role in maintaining a balanced microbiota composition (35,36,(46)(47)(48). Depletion of a-defensins is associated with gut microbiota dysbiosis and endotoxemia (49,50). Total body irradiation at a sublethal dose decreases intestinal mucosal macrophages, neutrophils, and lymphocytes (27).…”

Section: Introductionmentioning

confidence: 99%

Paneth cell dysfunction in radiation injury and radio-mitigation by human α-defensin 5

Shukla,

Rao,

Meena

et al. 2023

Front. Immunol.

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IntroductionThe mechanism underlying radiation-induced gut microbiota dysbiosis is undefined. This study examined the effect of radiation on the intestinal Paneth cell α-defensin expression and its impact on microbiota composition and mucosal tissue injury and evaluated the radio-mitigative effect of human α-defensin 5 (HD5).MethodsAdult mice were subjected to total body irradiation, and Paneth cell α-defensin expression was evaluated by measuring α-defensin mRNA by RT-PCR and α-defensin peptide levels by mass spectrometry. Vascular-to-luminal flux of FITC-inulin was measured to evaluate intestinal mucosal permeability and endotoxemia by measuring plasma lipopolysaccharide. HD5 was administered in a liquid diet 24 hours before or after irradiation. Gut microbiota was analyzed by 16S rRNA sequencing. Intestinal epithelial junctions were analyzed by immunofluorescence confocal microscopy and mucosal inflammatory response by cytokine expression. Systemic inflammation was evaluated by measuring plasma cytokine levels.ResultsIonizing radiation reduced the Paneth cell α-defensin expression and depleted α-defensin peptides in the intestinal lumen. α-Defensin down-regulation was associated with the time-dependent alteration of gut microbiota composition, increased gut permeability, and endotoxemia. Administration of human α-defensin 5 (HD5) in the diet 24 hours before irradiation (prophylactic) significantly blocked radiation-induced gut microbiota dysbiosis, disruption of intestinal epithelial tight junction and adherens junction, mucosal barrier dysfunction, and mucosal inflammatory response. HD5, administered 24 hours after irradiation (treatment), reversed radiation-induced microbiota dysbiosis, tight junction and adherens junction disruption, and barrier dysfunction. Furthermore, HD5 treatment also prevents and reverses radiation-induced endotoxemia and systemic inflammation.ConclusionThese data demonstrate that radiation induces Paneth cell dysfunction in the intestine, and HD5 feeding prevents and mitigates radiation-induced intestinal mucosal injury, endotoxemia, and systemic inflammation.

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Section: Introductionmentioning

confidence: 99%

Paneth cell dysfunction in radiation injury and radio-mitigation by human α-defensin 5

Shukla,

Rao,

Meena

et al. 2023

Front. Immunol.

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“…In addition to autophagy, AMP expression and lysozyme sorting are also regulated by NOD2, suggesting the crucial role of NOD2 in the pathogenesis of CD (49,50). In Caco-2 cells and the ileum of CD patients, the abnormality of NOD2 is associated with the reduced expression of a-defensins, but not lysozyme (50,51). ATG16L1/XBP1 knockout mice develop higher level of intestinal inflammation than mice with ATG16L1 or XBP1 deletion, pointing out the compensatory interaction between autophagy and UPR (16).…”

Section: Pcs In Inflammatory Bowel Diseasementioning

confidence: 99%

Multifaceted involvements of Paneth cells in various diseases within intestine and systemically

Cui

Wang²,

Li³

et al. 2023

Front. Immunol.

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Serving as the guardians of small intestine, Paneth cells (PCs) play an important role in intestinal homeostasis maintenance. Although PCs uniquely exist in intestine under homeostasis, the dysfunction of PCs is involved in various diseases not only in intestine but also in extraintestinal organs, suggesting the systemic importance of PCs. The mechanisms under the participation of PCs in these diseases are multiple as well. The involvements of PCs are mostly characterized by limiting intestinal bacterial translocation in necrotizing enterocolitis, liver disease, acute pancreatitis and graft-vs-host disease. Risk genes in PCs render intestine susceptible to Crohn’s disease. In intestinal infection, different pathogens induce varied responses in PCs, and toll-like receptor ligands on bacterial surface trigger the degranulation of PCs. The increased level of bile acid dramatically impairs PCs in obesity. PCs can inhibit virus entry and promote intestinal regeneration to alleviate COVID-19. On the contrary, abundant IL-17A in PCs aggravates multi-organ injury in ischemia/reperfusion. The pro-angiogenic effect of PCs aggravates the severity of portal hypertension. Therapeutic strategies targeting PCs mainly include PC protection, PC-derived inflammatory cytokine elimination, and substituting AMP treatment. In this review, we discuss the influence and importance of Paneth cells in both intestinal and extraintestinal diseases as reported so far, as well as the potential therapeutic strategies targeting PCs.

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“…The fi nding that NOD2 governs expression of a key subset of α -defensins in mice [29] suggests the possibility that lowered α -defensin expression could be associated with Crohn ' s disease, one type of IBD that is linked to loss -of function mutations in NOD2. Indeed, analysis of α -defensin expression in Crohn ' s disease ( CD ) patients, in particular those harboring NOD2 mutations, showed reduced α -defensin expression [43] . These fi ndings suggest a model in which NOD2 mutations result in reduced α -defensin production and a subsequent defective defense against the normal fl ora.…”

Section: Intestinal Crypts P Aneth Cells and Antimicrobialsmentioning

confidence: 99%

Anatomy of the Gut Barrier and Establishment of Intestinal Homeostasis

Sellge

Schnupf

Sansonetti

2010

Bacterial Virulence

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Pathomechanismus des Morbus Crohn mit NOD-2 (CARD 15) Mutation: defiziente mukosale Defensinexpression bei intakter Zytokinexpression

Cited by 4 publications

References 0 publications

Paneth cell dysfunction in radiation injury and radio-mitigation by human α-defensin 5

Paneth cell dysfunction in radiation injury and radio-mitigation by human α-defensin 5

Multifaceted involvements of Paneth cells in various diseases within intestine and systemically

Anatomy of the Gut Barrier and Establishment of Intestinal Homeostasis

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