Gut Peri-Cryptal Fibroblasts Re-Program Intestinal Stem Cells via Interleukin-33

The  small  intestine  comprises  an  array  of  epithelial  cells  that  serves  distinct functions  during  its  time  course.  Many  pathways  are  known  to  regulate  this  programming  of  intestinal  stem  cell.  The balance between epithelium and type 2 cytokines like IL-33 is known to play major role in intestinal homeostasis. However, under  pathological  conditions  the  intestinal  epithelium  is  forced  to  undergo  many  changes eventually  disrupting  harmony. We  generated  an  inducible  transgenic  mouse  expressing  IL-33  specifically  in  gut (IL-33Vcre).  To  analyze  the  role  of  IL-33  on  epithelium  directly we  used  the  in-vitro  cultivation  of  organoids  from  C5BL/6 mice.  Localization of IL-33 was studied in IL-33^LacZ/LacZ reporter mice.  We  observed  high  expression  of  IL-33  in  the  gut  of  TLR-ligand  challenged  mice and  specific  expression of IL-33  by  sub-epithelial myofibroblasts in the vicinity of stem cells.  IL-33Vcre mice led to an increased expression of anti-microbial peptides and goblet cell markers. Signaling  of  IL-33  into  intestinal  epithelial  cells (IEC)  in-  vivo  and  in  organoid  cultures  in-vitro  was  associated  with  altered  Notch  signaling  governing  proliferation  and  differentiation  of  IECs. Our  data  demonstrate  a  novel  mechanism  of  IL-33 signaling  and  its  significant  consequences on IEC function.  Therefore  it  plays  a  role  in  protecting barrier and  tackling  foreign  challenges.