Virus-Plus-Susceptibility Gene Interaction Determines Crohn's Disease Gene Atg16L1 Phenotypes in Intestine

Cadwell, Ken; Patel, Khushbu; Maloney, Nicole S.; Liu, Ta‐Chiang; Ng, Aylwin; Storer, Chad; Head, Richard D.; Xavier, Ramnik J.; Stappenbeck, Thaddeus S.; Virgin, Herbert W.

doi:10.1016/j.cell.2010.05.009

Cited by 809 publications

(809 citation statements)

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“…A20 deficiency in IECs does not cause spontaneous Paneth cell defects, but sensitizes their apoptotic loss in inflammatory conditions, either by direct low-dose TNF exposure or by exposure to cytokines produced by hyperactive A20-deficient myeloid cells, including TNF and IFNg. Both these cytokines are well known for their cytotoxic activities on IECs and may contribute to the development of intestinal inflammation through their direct activity on Paneth cells [39][40][41] . Also goblet cells are severely affected in A20 IEC/myel-KO mice, compromising the protective epithelial mucus layer.…”

Section: Discussionmentioning

confidence: 99%

A20 controls intestinal homeostasis through cell-specific activities

et al. 2014

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The transcription factor NF-kB is indispensable for intestinal immune homeostasis, but contributes to chronic inflammation and inflammatory bowel disease (IBD). A20, an inhibitor of both NF-kB and apoptotic signalling, was identified as a susceptibility gene for multiple inflammatory diseases, including IBD. Despite absence of spontaneous intestinal inflammation in intestinal epithelial cell (IEC) specific A20 knockout mice, we found additional myeloid-specific A20 deletion to synergistically drive intestinal pathology through cell-specific mechanisms. A20 ensures intestinal barrier stability by preventing cytokine-induced IEC apoptosis, while A20 prevents excessive cytokine production in myeloid cells. Combining IEC and myeloid A20 deletion induces ileitis and severe colitis, characterized by IEC apoptosis, Paneth and goblet cell loss, epithelial hyperproliferation and intestinal microbiota dysbiosis. Continuous epithelial cell death and regeneration in an inflammatory environment sensitizes cells for neoplastic transformation and the development of colorectal tumours in aged mice.

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Section: Discussionmentioning

confidence: 99%

A20 controls intestinal homeostasis through cell-specific activities

et al. 2014

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“…36,63,64 Here, we directly demonstrated aggravated experimental colitis in myeloid cell-specific autophagy-knockout mice, leading to increased mortality. In addition, we observed apparently increased colonic tissue expression of pro-Il1b and Il6 that are important players in colitis of DSS-treated Atg7 cKO mice compared to Atg7 cWT mice, [36][37][38] while the induction of Il6 was marginal.…”

Section: Figure 7 Systemic Inflammation and Bacterial Invasion Aftermentioning

confidence: 99%

Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis

et al. 2016

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(2016) Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis, Autophagy, 12:8, 1390-1403, DOI: 10.1080/15548627.2016 ABSTRACT Autophagy, which is critical for the proper turnover of organelles such as endoplasmic reticulum and mitochondria, affects diverse aspects of metabolism, and its dysregulation has been incriminated in various metabolic disorders. However, the role of autophagy of myeloid cells in adipose tissue inflammation and type 2 diabetes has not been addressed. We produced mice with myeloid cell-specific deletion of Atg7 (autophagy-related 7), an essential autophagy gene (Atg7 conditional knockout [cKO] mice). While Atg7 cKO mice were metabolically indistinguishable from control mice, they developed diabetes when bred to ob/w mice (Atg7 cKO-ob/ob mice), accompanied by increases in the crown-like structure, inflammatory cytokine expression and inflammasome activation in adipose tissue. Mfs (macrophages) from Atg7 cKO mice showed significantly higher interleukin 1 b release and inflammasome activation in response to a palmitic acid plus lipopolysaccharide combination. Moreover, a decrease in the NAD C :NADH ratio and increase in intracellular ROS content after treatment with palmitic acid in combination with lipopolysaccharide were more pronounced in Mfs from Atg7 cKO mice, suggesting that mitochondrial dysfunction in autophagy-deficient Mfs leads to an increase in lipid-induced inflammasome and metabolic deterioration in Atg7 cKO-ob/ob mice. Atg7 cKO mice were more susceptible to experimental colitis, accompanied by increased colonic cytokine expression, T helper 1 skewing and systemic bacterial invasion. These results suggest that autophagy of Mfs is important for the control of inflammasome activation in response to metabolic or extrinsic stress, and autophagy deficiency in Mfs may contribute to the progression of metabolic syndrome associated with lipid injury and colitis.

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“…Ultimately, this defi ciency results in defects in antigen presentation through the major histocompatability complex, decreased immune activation, and increased bacterial persistence in the gut mucosa ( 38 ). Recent in vivo murine studies demonstrate that the abnormal Paneth cell phenotype found with defective ATG16L1 function is the result of specifi c infection with a murine noravirus species, showing requisite genetic / microbial interactions that have important implications for human Crohn ' s disease ( 39 ).…”

Section: Host Genetic Defects In Containing Commensal Microbiotamentioning

confidence: 99%