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Controlling inflammation and cell death at the intestinal epithelial interface and beyond: lessons from conditional A20 knockout mice

Lars Vereecke (UGent)
(2011)
Author
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(UGent) and (UGent)
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Abstract
The ubiquitin-editing protein A20 (TNFAIP3) is a key player in termination of NF-κB signaling, and thereby prevents detrimental excessive NF-κB activation. In addition, A20 also exerts anti-apoptotic activity in specific cellular conditions. The physiological relevance of A20 as an anti-inflammatory protein is clearly demonstrated by the phenotype of A20 deficient mice, which are cachexic and develop severe multi-organ inflammation causing premature lethality. The immune regulating role of A20 was further underscored in genetic studies, where multiple polymorphisms in the A20 locus were associated with a wide range of inflammatory and auto-immune diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, celiac disease, and type 1 diabetes. To study the role of A20 in adult mice and in the context of inflammatory disease pathology, we generated conditional A20 knockout mice. Given the complex interaction between commensal bacteria, intestinal epithelial cells (IECs) and mucosal immune cells in establishing immune homeostasis in the gut, we examined the (patho)-physoliological functions of A20 in intestinal biology. We first generated IEC-specific A20 knockout mice (A20IEC-KO mice) and showed that these mice develop normally but have increased susceptibility to experimental colitis and are hypersensitive to recombinant TNF which induces massive IEC apoptosis, compromising intestinal barrier integrity leading to bacteremia and lethal sepsis. These findings identify A20 as a predominant anti-apoptotic protein in enterocytes, essential for maintenance of epithelial barrier integrity in conditions of intestinal injury and inflammation. We also evaluated myeloid-specific A20 knockout mice (A20myel-KO mice) in intestinal biology. A20myel-KO mice have an expansion of myeloid cells and spontaneously produce elevated serum titers of pro-inflammatory cytokines, including TNF and IL-6, and macrophages derived from these mice show hyperactive NF-κB responses in vitro. A20myel-KO mice spontaneously develop severe destructive polyarthritis but do not develop obvious signs of inflammation in other tissues, including the intestine. With this doctoral thesis, we have gained insight into the in vivo functions of A20 in intestinal physiology and inflammation. In addition, our conditional A20 knockout mice represent a new mouse model for the study of intestinal inflammation.
Keywords
A20, Inflammation, apoptosis, intestine

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Citation

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Chicago
Vereecke, Lars. 2011. “Controlling Inflammation and Cell Death at the Intestinal Epithelial Interface and Beyond: Lessons from Conditional A20 Knockout Mice”. Ghent, Belgium: Ghent University. Faculty of Sciences.
APA
Vereecke, L. (2011). Controlling inflammation and cell death at the intestinal epithelial interface and beyond: lessons from conditional A20 knockout mice. Ghent University. Faculty of Sciences, Ghent, Belgium.
Vancouver
1.
Vereecke L. Controlling inflammation and cell death at the intestinal epithelial interface and beyond: lessons from conditional A20 knockout mice. [Ghent, Belgium]: Ghent University. Faculty of Sciences; 2011.
MLA
Vereecke, Lars. “Controlling Inflammation and Cell Death at the Intestinal Epithelial Interface and Beyond: Lessons from Conditional A20 Knockout Mice.” 2011 : n. pag. Print.
@phdthesis{1252844,
  abstract     = {The ubiquitin-editing protein A20 (TNFAIP3) is a key player in termination of NF-\ensuremath{\kappa}B signaling, and thereby prevents detrimental excessive NF-\ensuremath{\kappa}B activation. In addition, A20 also exerts anti-apoptotic activity in specific cellular conditions. The physiological relevance of A20 as an anti-inflammatory protein is clearly demonstrated by the phenotype of A20 deficient mice, which are cachexic and develop severe multi-organ inflammation causing premature lethality. The immune regulating role of A20 was further underscored in genetic studies, where multiple polymorphisms in the A20 locus were associated with a wide range of inflammatory and auto-immune diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, celiac disease, and type 1 diabetes. To study the role of A20 in adult mice and in the context of inflammatory disease pathology, we generated conditional A20 knockout mice. Given the complex interaction between commensal bacteria, intestinal epithelial cells (IECs) and mucosal immune cells in establishing immune homeostasis in the gut, we examined the (patho)-physoliological functions of A20 in intestinal biology. We first generated IEC-specific A20 knockout mice (A20IEC-KO mice) and showed that these mice develop normally but have increased susceptibility to experimental colitis and are hypersensitive to recombinant TNF which induces massive IEC apoptosis, compromising intestinal barrier integrity leading to bacteremia and lethal sepsis. These findings identify A20 as a predominant anti-apoptotic protein in enterocytes, essential for maintenance of epithelial barrier integrity in conditions of intestinal injury and inflammation. We also evaluated myeloid-specific A20 knockout mice (A20myel-KO mice) in intestinal biology. A20myel-KO mice have an expansion of myeloid cells and spontaneously produce elevated serum titers of pro-inflammatory cytokines, including TNF and IL-6, and macrophages derived from these mice show hyperactive NF-\ensuremath{\kappa}B responses in vitro. A20myel-KO mice spontaneously develop  severe destructive polyarthritis but do not develop obvious signs of inflammation in other tissues, including the intestine. With this doctoral thesis, we have gained insight into the in vivo functions of A20 in intestinal physiology and inflammation. In addition, our conditional A20 knockout mice represent a new mouse model for the study of intestinal inflammation.},
  author       = {Vereecke, Lars},
  keyword      = {A20,Inflammation,apoptosis,intestine},
  language     = {eng},
  pages        = {188},
  publisher    = {Ghent University. Faculty of Sciences},
  school       = {Ghent University},
  title        = {Controlling inflammation and cell death at the intestinal epithelial interface and beyond: lessons from conditional A20 knockout mice},
  year         = {2011},
}