SHP-2 Phosphatase Prevents Colonic Inflammation by Controlling Secretory Cell Differentiation and Maintaining Host-Microbiota Homeostasis.
Polymorphisms in the PTPN11 gene encoding for the tyrosine phosphatase SHP-2 were described in patients with ulcerative colitis. We have recently demonstrated that mice with an intestinal epithelial cell-specific deletion of SHP-2 (SHP-2(IEC-KO) ) develop severe colitis 1 month after birth. However, the mechanisms by which SHP-2 deletion induces colonic inflammation remain to be elucidated. We generated SHP-2(IEC-KO) mice lacking Myd88 exclusively in the intestinal epithelium. The colonic phenotype was histologically analyzed and cell differentiation was determined by electron microscopy and lysozyme or Alcian blue staining. Microbiota composition was analyzed by 16S sequencing. Results show that innate defense genes including those specific to Paneth cells were strongly up-regulated in SHP-2-deficient colons. Expansion of intermediate cells (common progenitors of the Goblet and Paneth cell lineages) was found in the colon of SHP-2(IEC-KO) mice whereas Goblet cell number was clearly diminished. These alterations in Goblet/intermediate cell ratio were noticed 2 weeks after birth, before the onset of inflammation and were associated with significant alterations in microbiota composition. Indeed, an increase in Enterobacteriaceae and a decrease in Firmicutes were observed in the colon of these mice, indicating that dysbiosis also occurred prior to inflammation. Importantly, loss of epithelial Myd88 expression inhibited colitis development in SHP-2(IEC-KO) mice, rescued Goblet/intermediate cell ratio, and prevented NFκB hyperactivation and inflammation. These data indicate that SHP-2 is functionally important for the maintenance of appropriate barrier function and host-microbiota homeostasis in the large intestine. J. Cell. Physiol. 231: 2529-2540, 2016. © 2016 The Authors. Journal of Cellular Physiology published by Wiley Periodicals, Inc.
Faculty of Medicine and Health Sciences, Department of Anatomy and Cell Biology, Cancer Research Pavilion, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Geneviève
G
Coulombe
Faculty of Medicine and Health Sciences, Department of Anatomy and Cell Biology, Cancer Research Pavilion, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Ariane
A
Langlois
Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
Giada
G
De Palma
Faculty of Medicine and Health Sciences, Department of Anatomy and Cell Biology, Cancer Research Pavilion, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Marie-Josée
MJ
Langlois
Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
Justin L
JL
McCarville
Faculty of Medicine and Health Sciences, Department of Anatomy and Cell Biology, Cancer Research Pavilion, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Jessica
J
Gagné-Sanfaçon
Faculty of Medicine and Health Sciences, Department of Anatomy and Cell Biology, Cancer Research Pavilion, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Nathalie
N
Perreault
Department of Pathology and Division of Biological Sciences, University of California San Diego, La Jolla, California.
Gen-Sheng
GS
Feng
Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
Premysl
P
Bercik
Faculty of Medicine and Health Sciences, Department of Anatomy and Cell Biology, Cancer Research Pavilion, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
François
F
Boudreau
Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
Elena F
EF
Verdu
Faculty of Medicine and Health Sciences, Department of Anatomy and Cell Biology, Cancer Research Pavilion, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Nathalie
N
Rivard
D000818:Animals; D000831:Animals, Newborn; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D003106:Colon / Q000473:pathology*; D020397:Goblet Cells / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis; D007249:Inflammation / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control*; D008810:Mice, Inbred C57BL; D064307:Microbiota; D009113:Muramidase / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D019879:Paneth Cells / Q000378:metabolism / Q000473:pathology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000172:deficiency / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
D023181:Antimicrobial Cationic Peptides; D015415:Biomarkers; D053594:Myeloid Differentiation Factor 88; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D009113:Muramidase