ena-STUDY-UNIVERSITY OF CALIFORNIA - SAN FRANCISCO-28-05-2019-16:07:55:380-521
A20 expression in dendritic cells restrains intestinal defensin expression and preserves commensal homeostasis
Microbial dysbiosis commonly occurs in patients with inflammatory bowel diseases (IBD).  Exogenous causes of dysbiosis such as antibiotics and diet are well described, but host derived causes are understudied.  A20 is a potent regulator of signals triggered by microbial pattern molecules, and A20 regulates susceptibility to intestinal inflammation in mice and in humans.  We now report that mice lacking A20 expression in dendritic cells, A20FL/FL CD11c-Cre mice, spontaneously develop colitogenic intestinal dysbiosis that is evident upon weaning and precedes the onset of colitis. Intestines from A20FL/FL CD11c-Cre mice express increased amounts of the defensins Reg3ß and Reg3?, but not Ang4.  A20 deficient DCs promote gut microbiota perturbation in the absence of adaptive lymphocytes.  Moreover, A20 deficient DCs directly induce expression of Reg3ß and Reg3? but not Ang 4 in normal intestinal epithelial cell enteroid cultures in the absence of other cell types.  These findings reveal a pathophysiological pathway in which defective expression of an IBD susceptibility gene in DCs drives aberrant defensin expression and luminal microbiota disturbance that in turn confers host susceptibility to intestinal inflammation.
Microbial dysbiosis commonly occurs in patients with inflammatory bowel diseases (IBD).  Exogenous causes of dysbiosis such as antibiotics and diet are well described, but host derived causes are understudied.  A20 is a potent regulator of signals triggered by microbial pattern molecules, and A20 regulates susceptibility to intestinal inflammation in mice and in humans.  We now report that mice lacking A20 expression in dendritic cells, A20FL/FL CD11c-Cre mice, spontaneously develop colitogenic intestinal dysbiosis that is evident upon weaning and precedes the onset of colitis. Intestines from A20FL/FL CD11c-Cre mice express increased amounts of the defensins Reg3ß and Reg3?, but not Ang4.  A20 deficient DCs promote gut microbiota perturbation in the absence of adaptive lymphocytes.  Moreover, A20 deficient DCs directly induce expression of Reg3ß and Reg3? but not Ang 4 in normal intestinal epithelial cell enteroid cultures in the absence of other cell types.  These findings reveal a pathophysiological pathway in which defective expression of an IBD susceptibility gene in DCs drives aberrant defensin expression and luminal microbiota disturbance that in turn confers host susceptibility to intestinal inflammation.